Nk-1 and serotonin transporter inhibitors

ABSTRACT

The invention encompasses compounds of Formula I, including pharmaceutically acceptable salts, their pharmaceutical compositions, and their use in treating disorders associated with an excess or imbalance of tachykinins or serotonin or both.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. provisional application No.60/792,604, filed Apr. 17, 2006.

BACKGROUND OF THE INVENTION

Tachykinins are a group of naturally occurring peptides found widelydistributed throughout mammals, both within the central nervous systemand in the peripheral nervous and circulatory systems. The three knownmammalian tachykinins are Neurokinin-1 (NK-1, substance P), NeurokininA, and Neurokinin B. These compounds act as neurotransmitters andimmunomodulators and may contribute to the pathophysiology of a widevariety of human diseases.

Receptors for tachykinins have been identified and include neurokinin-1(NK-1 or Substance P-preferring), NK-2 (Neurokinin A-preferring) andNK-3 (Neurokinin B-preferring). NK-1 receptor antagonists are beingdeveloped for the treatment of physiological conditions associated withan excess or imbalance of tachykinins, particularly substance P. Suchconditions include affective disorders such as anxiety, depression,obsessive compulsive disorder, bulimia, and panic disorder. See Gentschet al. Behav. Brain Res. 2002, 133, 363; Varty et al.Neuropsychopharmacology 2002, 27, 371; Papp et al. Behav. Brain Res.2000, 115, 19; Kramer et al. Science 1998, 281, 1640; and Rosen et al.Bioorg. Med. Chem. Lett. 1998, 8, 281.

NK-1 antagonists are believed to modulate 5-HT function vianoradrenergic pathways and have been shown to attenuate presynaptic5-HT_(1A) receptor function. Thus, the combination of serotonin reuptakeinhibition with NK-1 antagonism may lead to new classes of drugs withimproved characteristics.

DESCRIPTION OF THE INVENTION

The invention encompasses compounds of Formula I, includingpharmaceutically acceptable salts, pharmaceutical compositions, andtheir use in treating disorders related to levels of tachykinins orserotonin or both.

One aspect of the invention are compounds of Formula I

where:

-   R¹ is hydrogen, alkyl, cycloalkyl, or benzyl;-   R² is hydrogen or alkyl;-   R³ is hydrogen or alkyl;-   R⁴ is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy,    cyano, or COR⁶;-   R⁵ is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy,    cyano, or COR⁶;-   R⁶ is hydroxy, alkoxy, benzyloxy, amino, alkylamino, dialkylamino,    pyrrolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl, or    morpholinyl;-   Ar¹ is phenyl or pyridinyl, and is substituted with 0-2 substituents    selected from the group consisting of halo, alkyl, haloalkyl, cyano,    phenyl and furanyl;-   Ar² is phenyl substituted with 1-5 substituents or is naphthyl    substituted with 0-3 substituents where the substituents are    selected from the group consisting of halo, alkyl, cycloalkyl,    haloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, haloalkoxy,    benzyloxy, alkylthio, cyano, nitro, amino, alkylamino, dialkylamino,    (alkylcarbonyl)amino, (alkoxycarbonyl)amino    (benzyloxycarbonyl)amino, carboxy, alkoxycarbonyl,    benzyloxycarbonyl, alkylSO₂, phenyl, phenoxy, acetyl, and formyl;-   or Ar² is furanyl, thienyl, pyrrolyl, isoxazolyl, isothiazolyl,    pyrazolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl,    thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl,    pyrmidinyl, pyrazinyl, triazinyl, quinolinyl, or isoquinolinyl, and    is substituted with 0-3 substituents selected from the group    consisting of amino, alkylamino, dialkylamino, oxo, halo, alkyl,    haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitro,    pyrrolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl, and    morpholinyl;-   or Ar² is benzodioxolyl, dibenzofuranyl, thianthrenyl, or    trimethylenedioxybenzen-yl;-   or a pharmaceutically acceptable salt thereof.

Another aspect of the invention are compounds of Formula I where

-   R¹ is hydrogen or alkyl;-   R⁴ is hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, or cyano;-   R⁵ is hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, or cyano;-   Ar¹ is phenyl substituted with 0-2 substituents selected from the    group consisting of halo, alkyl, haloalkyl, and cyano;-   Ar² is phenyl substituted with 1-3 substituents or is naphthyl    substituted with 0-3 substituents where the substituents are    selected from the group consisting of halo, alkyl, haloalkyl,    hydroxyalkyl, hydroxy, alkoxy, alkoxyalkyl, haloalkoxy, alkylthio,    cyano, nitro, amino, alkylamino, dialkylamino, phenyl, phenoxy,    acetyl, and formyl;-   or Ar² is furanyl, thienyl, pyrrolyl, isoxazolyl, isothiazolyl,    pyrazolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl,    thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl,    pyrmidinyl, triazinyl, quinolinyl, or isoquinolinyl, and is    substituted with 0-3 substituents selected from the group consisting    of amino, alkylamino, dialkylamino, oxo, halo, alkyl, haloalkyl,    alkoxy, alkylthio, haloalkoxy, cyano, nitro, pyrrolidinyl,    piperidinyl, piperazinyl, N-alkylpiperazinyl, or morpholinyl;-   or Ar² is benzodioxolyl, dibenzofuranyl or thianthrenyl.

Another aspect of the invention are compounds of Formula I where R¹ ishydrogen.

Another aspect of the invention are compounds of Formula I where R² andR³ are hydrogen.

Another aspect of the invention are compounds of Formula I where R² ismethyl and R³ is hydrogen.

Another aspect of the invention are compounds of Formula I where Ar¹ isphenyl.

Another aspect of the invention are compounds of Formula I where Ar² isphenyl substituted with 1-5 substituents or is naphthyl substituted with0-3 substituents where the substituents are selected from the groupconsisting of halo, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, hydroxy, alkoxy, haloalkoxy, benzyloxy, alkylthio, cyano,nitro, amino, alkylamino, dialkylamino, (alkylcarbonyl)amino,(alkoxycarbonyl)amino (benzyloxycarbonyl)amino, carboxy, alkoxycarbonyl,benzyloxycarbonyl, alkylSO₂, phenyl, phenoxy, acetyl, and formyl.

Another aspect of the invention are compounds of Formula I where Ar² isphenyl substituted with 1-3 substituents or is naphthyl substituted with0-3 substituents where the substituents are selected from the groupconsisting of halo, alkyl, haloalkyl, hydroxyalkyl, hydroxy, alkoxy,alkoxyalkyl, haloalkoxy, alkylthio, cyano, nitro, amino, alkylamino,dialkylamino, phenyl, phenoxy, acetyl, and formyl.

Another aspect of the invention are compounds of Formula I where Ar² isfuranyl, thienyl, pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl,oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl,tetrazolyl, pyridinyl, pyridazinyl, pyrmidinyl, pyrazinyl, triazinyl,quinolinyl, or isoquinolinyl, and is substituted with 0-3 substituentsselected from the group consisting of amino, alkylamino, dialkylamino,oxo, halo, alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano,nitro, pyrrolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl, andmorpholinyl.

Another aspect of the invention are compounds of Formula I where Ar² isfuranyl, thienyl, pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl,oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl,tetrazolyl, pyridinyl, pyridazinyl, pyrmidinyl, triazinyl, quinolinyl,or isoquinolinyl, and is substituted with 0-3 substituents selected fromthe group consisting of amino, alkylamino, dialkylamino, oxo, halo,alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitro,pyrrolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl, ormorpholinyl.

Another aspect of the invention are compounds of Formula I where Ar² isfuranyl, thienyl, pyrazolyl, thiazolyl, imidazolyl, tetrazolyl,pyridinyl, pyrmidinyl, quinolinyl, or isoquinolinyl and is substitutedwith 0-3 substituents selected from the group consisting of halo, alkyl,haloalkyl, alkoxy, haloalkoxy, or cyano.

Any scope of any substituent, including R¹, R², R³, R⁴, R⁵, R⁶, Ar¹, orAr², can be used independently with the scope of any other instance of asubstituent.

Unless specified otherwise, these terms have the following meanings.“Alkyl” means a straight or branched alkyl group composed of 1 to 6carbons. “Alkenyl” means a straight or branched alkyl group composed of2 to 6 carbons with at least one double bond. “Cycloalkyl” means amonocyclic ring system composed of 3 to 7 carbons. “Hydroxyalkyl,”“alkoxy” and other terms with a substituted alkyl moiety includestraight and branched isomers composed of 1 to 6 carbon atoms for thealkyl moiety. “Haloalkyl” and “haloalkoxy” include all halogenatedisomers from monohalo substituted alkyl to perhalo substituted alkyl.“Aryl” includes carbocyclic and heterocyclic aromatic substituents.Parenthetic and multiparenthetic terms are intended to clarify bondingrelationships to those skilled in the art. For example, a term such as((R)alkyl) means an alkyl substituent further substituted with thesubstituent R.

Trimethylenedioxybenzen-yl means

The invention includes all pharmaceutically acceptable salt forms of thecompounds. Pharmaceutically acceptable salts are those in which thecounter ions do not contribute significantly to the physiologicalactivity or toxicity of the compounds and as such function aspharmacological equivalents. These salts can be made according to commonorganic techniques employing commercially available reagents. Someanionic salt forms include acetate, acistrate, besylate, bromide,chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride,hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate,phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Somecationic salt forms include ammonium, aluminum, benzathine, bismuth,calcium, choline, diethylamine, diethanolamine, lithium, magnesium,meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium,tromethamine, and zinc.

Some Formula I compounds contain at least one asymmetric carbon atom, anexample of which is shown below. The invention includes allstereoisomeric forms of the compounds, both mixtures and separatedisomers. Mixtures of stereoisomers can be separated into individualisomers by methods known in the art.

Synthetic Methods

Compounds of Formula I can be made according to methods known in the artand those illustrated in the schemes below and in the specificembodiments section. The schemes encompass reasonable variations knownin the art. The variables describing general structural formulas andfeatures in the synthetic schemes are distinct from and should not beconfused with the variables in the claims or the rest of thespecification. These variables are meant only to illustrate how to makesome of the compounds of this invention.

Biological Methods

NK-1 Binding assay. U373 cells, a human glioblastoma-astrocytoma cellline that endogenously expresses the neurokinin-1 (NK-1) receptor, weregrown in a monolayer culture at 37° C. in 5% CO₂ and fed with MinimumEssential Medium (MEM) supplemented with 10% fetal bovine serum.Membranes were prepared as follows: Cells were washed twice withice-cold phosphate-buffered saline (pH 7.4) and then incubated for 5-10minutes with ice-cold 10 mM Tris buffer (pH 7.4) containing 5 mM EDTA.Cells were removed from plates, homogenized, and centrifuged at 32,000×gfor 20 minutes. The resulting supernatant was discarded, and the pelletresuspended by homogenization in 50 mM Tris buffer (pH 7.4) containing 1mM EDTA and centrifuged at 32,000×g for 20 minutes. The resultingsupernatant was discarded, and the pellet resuspended by homogenizationin NK-1 binding assay buffer (50 mM Tris-HCL (pH 7.4), 3 mM MnCl2, 200μg/ml BSA, 5 μg/ml chymostatin, 40 μg/ml bacitracin and 4 μg/mlleupeptin).

On the day of an experiment the membrane preparation was thawed,homogenized and diluted with NK-1 binding assay buffer to theappropriate concentration. Competition binding assays were performed in96 well plate format by incubating membranes (5-10 μg/well) with BoltonHunter labeled [¹²⁵I] Substance P, at a concentration of 200 nM, andconcentrations of drugs ranging from 10000 to 0.01 nM. Samples wereincubated for 30 min at 20° C. then filtered through GF/B glass fiberfilters (pretreated with 1% polyethyleneimine and 0.3% Triton X-100)using a Brandel cell harvester. The filters were then washed with 10 mlice cold 50 mM Tris-HCL (pH 7.4) containing 3 mM MgCl₂. Non-specific wasdefined in the presence of 2 μM L-733,060 (a non-peptide NK-1antagonist). The amount of radioligand bound in the presence and absenceof competitor was analyzed by plotting (-)log drug concentration versusthe amount of radioligand specifically bound. The midpoint of thedisplacement curve (IC₅₀, nM), signifies the potency. Ki values can becalculated using the method of Cheng and Prusoff (Cheng and Prusoff,BiochemicalPharmacology, Vol 22, pp. 3099-3108, Pergamon Press (1973)).

Serotonin transporter binding assay. HEK-293 cells that stably expresshuman serotonin transporters (HEK-hSERT cells) were grown at 37° C. in5% CO₂ as a monolayer in medium consisting of EMEM supplemented with 10%fetal bovine serum and G418 sulfate (500 μg/ml). To prepare membranesfor radioligand binding experiments, cells were rinsed twice withphosphate-buffered saline (138 mM NaCl, 4.1 mM KCl, 5.1 mM Na₂PO₄, 1.5mM KH₂PO₄, 11.1 mM glucose, pH 7.4). Cells were transferred from platesto polypropylene tubes (16×100 mm), centrifuged at 1,200×g for 5 min andwere frozen at −80° C. until assay. Following centrifugation, pelletswere resuspended by homogenization in buffer consisting of 50 mM Tris(pH 7.7 at 25° C.), 120 mM NaCl and 5 mM KCl and then centrifuged at32,000×g for 10 min. Following centrifugation, supernatants werediscarded and pellets were resuspended in buffer consisting of 50 mMTris (pH 7.4 at 25° C.), 150 mM NaCl and 5 mM KCl. Membrane homogenates(200 μl/plate) were incubated with 1 nM [³H]-citalopram (specificactivity=85 Ci/mmol) and increasing concentrations of test compounds for1 hr at 25° C. in a total volume of 250 μl. The assay buffer consistedof 50 mM Tris (pH 7.4 at 25° C.), 120 mM NaCl and 5 mM KCl (pH 7.4 withconc. HCl). Plates were incubated for 1 hr at 25° C., then filteredthrough 0.5% PEI treated Whatman GF/B filters using a Brandel cellharvester. Filters were washed three times with 3 ml of ice-cold triswash buffer. Non-specific binding was defined with 10 μM fluoxetine.Amount of radioligand bound in the presence and absence of competitorwas analyzed by plotting (-)log drug concentration versus the amount ofradioligand specifically bound. The midpoint of the displacement curve(IC₅₀, nM), signifies the potency. Ki values can be calculated using themethod of Cheng and Prusoff (Cheng and Prusoff, BiochemicalPharmacology,Vol 22, pp. 3099-3108, Pergamon Press (1973)). NK-1 and serotonintransporter binding results are shown in Tables 1 and 2. TABLE 1Structure NK-1 IC₅₀ (nM) SERT IC₅₀ (nM)

A A

C A

A A

A A

A A

A A

A A

A A

C B

A A

B A

C A

C B

A A

B A

B A

A A

B A

A A

A A

A A

A A

C A

A A

A A

A A

C B

A A

A A

A A

A A

A A

A A

B B

B A

C C

B A

A A

B A

C B

— —

A A

C A

A A

A A

B B

B A

A A

A A

A A

A A

C A

A A

A A

A A

A A

— —

A B

C B

B B

A A

C C

A A

A A

A A

A A

A A

B A

B A

C A

— —

B B

B A

B A

B B

A A

B A

C C

C A

C A

A A

A A

A A

A A

A A

A A

B A

C A

B A

A A

A A

C A

C B

B A

A A

A A

B A

A A

C A

B A

A A

A A

A A

A A

A A

A A

A A

A A

A AValues: A = 0.01-100 nM; B = 100-300 nM; C > 300 nM.

TABLE 2 Structure NK-1 IC₅₀ (nM) SERT IC₅₀ (nM)

A A

A A

C A

A A

B A

A A

C A

C B

A A

A A

C A

C A

B A

B A

C B

A A

A A

A A

B A

A A

A A

C A

A A

B A

C A

A A

A A

C B

C A

C A

A A

B B

C A

B A

B B

C B

A A

C B

B A

A A

C B

C A

C A

A A

A A

C B

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A B

A A

C A

A A

B A

A A

A A

A A

A C

A C

A C

A A

A A

C A

C A

C A

C A

A A

C A

A A

A C

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A B

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A B

A AValues: A = 0.01-100 nM; B = 100-300 nM; C > 300 nM.

Pharmaceutical Composition and Methods of Use

The compounds of Formula I demonstrate inhibition of neurokinin-1 orserotonin reuptake or both. Inhibition of these receptors correlateswith efficacy for affective disorders such as anxiety, depression,obsessive compulsive disorder, bulimia, and panic disorder. As such, thecompounds of Formula I can be useful for the treatment of thesedisorders and other aspects of the invention are compositions andmethods of using the compounds to treat these conditions and otherconditions associated with aberrant levels of tachykinins or serotoninor both.

The compounds of this invention are generally given as pharmaceuticalcompositions comprised of a therapeutically effective amount of acompound of Formula I, or a pharmaceutically acceptable salt, and apharmaceutically acceptable carrier and may contain conventionalexipients. A therapeutically effective amount is the amount needed toprovide a meaningful patient benefit as determined by practitioners inthat art. Pharmaceutically acceptable carriers are those conventionallyknown carriers having acceptable safety profiles. Compositions encompassall common solid and liquid forms including capsules, tablets, losenges,and powders as well as liquid suspensions, syrups, elixers, andsolutions. Compositions are made using common formulation techniques andconventional excipients (such as binding and wetting agents) andvehicles (such as water and alcohols).

Solid compositions are normally formulated in dosage units providingfrom about 1 to about 1000 mg of the active ingredient per dose. Someexamples of solid dosage units are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg,and 1000 mg. Liquid compositions are generally in a unit dosage range of1-100 mg/mL. Some examples of liquid dosage units are 1 mg/mL, 10 mg/mL,25 mg/mL, 50 mg/mL, and 100 mg/mL. Generally, the dosage unit will be ina unit range similar to agents of that class used clinically, forexample fluoxetine.

The invention encompasses all conventional modes of administration; oraland parenteral methods are preferred. Generally, the dosing regimen willbe similar to agents of that class used clinically, for examplefluoxetine. Typically, the daily dose will be 0.01-100 mg/kg body weightdaily. Generally, more compound is required orally and lessparenterally. The specific dosing regime, however, should be determinedby a physician using sound medical judgment.

Tachykinin and serotonin modulators are associated with depression.Accordingly, another aspect of the invention are methods for treatingdepressive disorders including Major Depressive Disorders (MDD), bipolardepression, unipolar depression, single or recurrent major depressiveepisodes, recurrent brief depression, catatonic features, melancholicfeatures including feeding disorders, such as anorexia, weight loss,atypical features, anxious depression, or postpartum onset. Othercentral nervous system disorders encompassed within the term MDD includeneurotic depression, post-traumatic stress disorders (PTSD) and socialphobia, with early or late onset dementia of the Alzheimer's type, withdepressed mood, vascular dementia with depressed mood, mood disordersand tolerance induced by drugs such as alcohol, amphetamines, cocaine,inhalants, opioids, sedatives, anxiolytics and other substances,schizoaffective disorder of the depressed type, and adjustment disorderwith depressed mood.

Tachykinin and serotonin modulators are also associated with thetreatment or prevention of schizophrenic disorders. Accordingly, anotheraspect of the invention are methods for treating schizophrenic disordersincluding paranoid schizophrenia, disorganized schizophrenia, catatonicschizophrenia, undifferentiated schizophrenia, residual schizophrenia.

Tachykinin and serotonin modulators are also associated with thetreatment or prevention of anxiety. Accordingly, another aspect of theinvention are methods for treating anxiety disorders including panicdisorders, agoraphobia, phobias, obsessive-compulsive disorder, stressdisorders including post-traumatic stress disorders, generalized anxietydisorders, acute stress disorders and mixed anxiety-depressiondisorders.

Tachykinin and serotonin modulators are also associated with thetreatment or prevention of cognitive disorders. Accordingly, anotheraspect of the invention are methods for treating cognitive disordersincluding dementia, and amnesia disorders. Tachykinin and serotoninmodulators are also associated with the treatment or prevention ofmemory and cognition in healthy humans.

Tachykinin and serotonin modulators are also associated with use asanalgesics. Accordingly, another aspect of the invention are methods fortreating pain, including the treatment of traumatic pain such aspostoperative pain, chronic pain such as arthritic pain such asoccurring in osteo-, rheumatoid or psoriatic arthritis, neuropathic painsuch as post-herpetic neuralgia, trigeminal neuralgia, segmental orintercostal neuralgia, fibromyalgia, peripheral neuropathy, diabeticneuropathy, chemotherapy-induced neuropathy, AIDS-related neuropathy,various forms of headache such as migraine, acute or chronic tensionheadache, cluster headaches, maxillary sinus pain, cancer pain, pain ofbodily origin, gastrointestinal pain, sport's injury pain,dysmennorrhoea, menstrual pain, meningitis, musculoskeletal pain, lowback pain e.g. spinal stenosis, prolapsed disc, sciatica, angina,ankylosing spondyolitis, gout, burns, scar pain, itch and thalamic painsuch as post stroke thalamic pain.

Tachykinin and serotonin modulators are also associated with thetreatment or prevention of sleep disorders. Accordingly, another aspectof the invention are methods for treating sleep disorders includinginsomnia, sleep apnea, narcolepsy, and circadian rhymic disorders.

Tachykinin and serotonin modulators are also associated with thetreatment or prevention of inflammation. Accordingly, another aspect ofthe invention are methods for treating inflammation, including thetreatment of inflammation in asthma, influenza and chronic bronchitis,in the treatment of inflammatory diseases of the gastrointestinal tractsuch as Crohn's disease, ulcerative colitis, inflammatory bowel diseaseand non-steroidal anti-inflammatory drug induced damage, inflammatorydiseases of the skin such as herpes and eczema, inflammatory diseases ofthe bladder such as cystitis and urge incontinence, and eye and dentalinflammation.

Tachykinin and serotonin modulators are also associated with thetreatment or prevention of allergic disorders. Accordingly, anotheraspect of the invention are methods for treating allergic disorders, inparticular allergic disorders of the skin such as urticaria, andallergic disorders of the airways such as rhinitis.

Tachykinin and serotonin modulators are also associated with thetreatment or prevention of emesis, nausea, retching and vomiting.Accordingly, another aspect of the invention are methods for treatingthese disorders.

Tachykinin and serotonin modulators are also associated with thetreatment or prevention of premenstrual dysphoric disorder (PMDD), inchronic fatigue syndrome and multiple sclerosis. Accordingly, anotheraspect of the invention are methods for treating these disorders.

DESCRIPTION OF SPECIFIC EMBODIMENTS

The following experimental procedures describe the synthesis of someFormula I compounds. Standard chemistry conventions are used in the textunless otherwise noted. The experimental encompass reasonable variationsknown in the art. Method A involves the use of a Suzuki coupling. MethodB involves the use of a Stille coupling. Method D involves reductiveamination. The following HPLC conditions were used in the preparing thecompounds below. HPLC method 1: Xterra C18 2.0×50 mm, A=95% H₂O/5% ACN,B=95% ACN/5% H₂O, Modifier 10 mM NH₄OAC, 1 mL/min, 0.00 min=10% B, 2.00min=100% B; HPLC method 2: Xterra C18 2.0×50 mm, A=95% H₂O/5% ACN, B=95%ACN/5% H₂O, Modifier 10 mM NH4OAC, Flow rate=1 mL/min, 0.00 min=10% B,0.80 min=60% B, 1.99 min=95% B, 2.00 min=100% B (1.5 mL/min); HPLCmethod 3: Phenomenex C18 4.6×50 mm, 10% MeOH/90% H₂O/0.1% TFA→90%MeOH/10% H₂O/0.1% TFA, Gradient time=4 min., Flow rate=4 mL/min; HPLCmethod 4: Phenomenex C18 4.6×50 mm, A=95% H₂O/5% ACN, B=95% ACN/5% H₂O,Modifier 10 mM NH₄OAc, 0.00 min=10% B, 3.5 min=95% B, Flow rate=1.5mL/min; HPLC method 5: Phenomenex Luna 3.0×50 mm, A=90% H₂O/10% MeOH,B=90% MeOH/10% H₂O, Modifier 0.1% TFA, 0.00 min=0% B, 4.0 min=100% B,Flow rate=4 mL/min; HPLC method 6: Xterra C18 2.1×50 mm, A=95% H₂O/5%ACN, B=95% ACN/5% H₂O, Modifier 10 mM NH₄OAc, 0.00 min=0% B, 0.80min=80% B, 2.00 min=100% B, Flow rate=1.0 mL/min.

tert-Butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate.4-Phenyl-4-piperidinecarboxylic acid p-methylbenzenesulfonate (19.0 g,50.3 mmol) was suspended in dry tetrahydrofuran (100 mL) and cooled to0° C. To this was added borane tetrahydrofuran complex (1 M in THF, 100mL, 100 mmol) cautiously over 15 min and the reaction mixture allowed towarm to room temperature overnight. The reaction mixture was cooled to0° C., treated with di-tert-butyl carbonate (15.0 g, 218 mmol) and 10 Nsodium hydroxide (12 mL), stirred at 0° C., and at room temperatureovernight. The reaction mixture was diluted with ethyl acetate, washedwith water (2×), brine (2×), dried over sodium sulfate and concentrated.The crude product was triturated with 10% ethyl acetate/hexanes solutionto afford 9.2 g (63%) of the title compound. ¹H-NMR (CD₃OD, 300 MHz) δ7.35-7.43 (m, 4H), 7.24-7.26 (m, 1H), 3.78-3.85 (m, 2H), 3.49 (s, 2H),2.97 (m, 2H), 2.17-2.21 (m, 2H), 1.77-1.87 (m, 2H), 1.46 (s, 9H). Massspec.: 292.17 (MH)⁺.

1-(tert-Butoxycarbonyl)-4-phenylpiperidine-4-carboxylic acid. To asuspension of 4-phenyl-4-piperidinecarboxylic acidp-methylbenzenesulfonate (100 g, 265 mmol) and triethylamine (111 mL,795 mmol) in tetrahydrofuran (1200 mL) was added di-tert-butyldicarbonate (63.6 g, 291 mmol). The reaction was slowly heated to agentle reflux and held there for 1 h. After one hour, gas evolution hadended and the reaction had become a clear solution. The reaction wascooled to room temperature and concentrated to remove most of thetetrahydrofuran. The residue was dissolved in water/ether and theaqueous made very basic by the addition of 10 M sodium hydroxide (50mL). The aqueous was washed with ether (2×) which was discarded. Theaqueous was transferred to an erlenmeyer flask and made acidic (ca. pH5) by addition of acetic acid to give a white precipitate. Theprecipitate was collected by filtration and air dried overnight to givea white powder. The last traces of water were removed under high vacuumto give the product (78.9 g, 258 mmol, 98% yield). ¹H-NMR (CD₃OD, 500MHz) δ 10.5 (bs, 1H), 7.39 (m, 2H), 7.33 (m, 2H), 7.26 (m, 1H), 3.90(bs, 2H), 3.08, (bs, 2H), 2.48 (d, J=13.4 Hz, 2H), 1.85 (m, 2H), 1.44(s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ ppm 179.6, 155.0, 141.6, 128.8,127.6, 126.1, 79.9, 49.3, 41.7, 33.4, 28.5. Mass spec.: 328.12 (MNa)⁺.

tert-Butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate. To asuspension of 1-(tert-butoxycarbonyl)-4-phenylpiperidine-4-carboxylicacid (40 g, 131 mmol) in tetrahydrofuran (131 mL) at room temperaturewas added borane tetrahydrofuran complex (1 M in tetrahydrofuran, 131mL, 131 mmol). There was effervescence and the substrate quickly wentinto solution. The reaction was stirred at room temperature for 3 days.The reaction was cooled to 0° C. and quenched by the cautious additionof 1 M sodium hydroxide. The reaction was diluted with ether, washedwith water (2×), then brine, dried over magnesium sulfate, andconcentrated. Trituration with 10% EtOAc/Hex (300 mL) gave a whitepowder which was collected by filtration to give 36.9 g (97%). ¹H-NMR(CD₃OD, 300 MHz) δ 7.35-7.43 (m, 4H), 7.24-7.26 (m, 1H), 3.78-3.85 (m,2H), 3.49 (s, 2H), 2.97 (m, 2H), 2.17-2.21 (m, 2H), 1.77-1.87 (m, 2H),1.46 (s, 9H). Mass spec.: 292.17 (MH)⁺.

tert-Butyl 4-(3-bromophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate.¹H-NMR (CDCl₃, 500 MHz) δ ppm 7.47 (s, 1H), 7.39 (m, 1H), 7.27 (m, 2H),3.72 (m, 2H), 3.55 (s, 2H), 3.06 (m, 2H), 2.05 (m, 2H), 1.76 (m, 2H),1.42 (s, 9H). Mass spec.: 370.12 (MH)⁺.

tert-Butyl 4-(3-chlorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate.¹H-NMR (CDCl₃, 500 MHz) δ ppm 7.30 (m, 2H), 7.23 (m, 2H), 3.72 (m, 2H),3.53 (s, 2H), 2.08 (m, 2H), 1.76 (m, 2H), 1.41 (s, 9H). Mass spec.:326.16 (MH)⁺.

tert-Butyl4-(3,4-difluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate. ¹H-NMR(CDCl₃, 500 MHz) δ ppm 7.10-7.18 (m, 2H), 7.05 (m, 1H), 3.68-3.73 (m,2H), 3.54 (m, 2H), 3.01-3.08 (m, 2H), 2.08 (m, 2H), 1.74-1.79 (m, 2H),1.42 (s, 9H).

tert-Butyl 4-(4-bromophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate.¹H-NMR (CDCl₃, 500 MHz) δ ppm 7.50 (m, 2H), 7.21 (m, 2H), 3.70 (m, 2H),3.53 (s, 2H), 3.02 (m, 2H), 2.10 (m, 2H), 1.75 (m, 2H), 1.42 (s, 9H).Mass spec.: 370.15 (MH)⁺.

tert-Butyl4-(hydroxymethyl)-4-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate.¹H-NMR (CDCl₃, 500 MHz) δ ppm 7.49-7.57 (m, 4H), 3.71-3.75 (m, 2H), 3.59(s, 2H), 3.01-3.10 (m, 2H), 2.15 (m, 2H), 1.85 (m, 2H), 1.42 (s, 9H).Mass spec.: 360.26 (MH)⁺.

tert-Butyl4-(hydroxymethyl)-4-(3-methoxyphenyl)piperidine-1-carboxylate. ¹H-NMR(CDCl₃, 500 MHz) δ ppm 7.31 (m, 1H), 6.87-6.93 (m, 1H), 6.88 (s, 1H),6.80 (m, 1H), 3.80 (s, 3 H), 3.72-3.78 (m, 2 H), 3.53 (d, J=6.41 Hz, 2H), 3.05 (t, J=11.14 Hz, 2 H), 2.14 (d, J=14.04 Hz, 2 H), 1.73 (ddd,J=14.11, 10.30, 3.97 Hz, 2 H), 1.42 (s, 9 H). Mass spec.: 322.22 (MH)⁺.

tert-Butyl4-(2-bromo-4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate.¹H-NMR (CDCl₃, 500 MHz) δ ppm 7.33-7.40 (m, 2H), 7.00-7.06 (m, 1H), 4.04(d, J=6.3 Hz, 2H), 3.59 (m, 2H), 3.19-3.26 (m, 2H), 2.45-2.49 (m, 2H),1.95-2.02 (m, 2H), 1.43 (s, 9H). Mass spec.: 390.15 (MH)⁺.

tert-Butyl4-(2,4-difluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate. ¹H-NMR(CDCl₃, 400 MHz) δ ppm7.22 (m, 1H), 6.85 (m, 1H), 6.77 (m, 1H), 3.70 (s,2H), 3.67 (m, 2H), 3.08 (m, 2H), 2.21 (m, 2H), 1.78 (m, 2H), 1.64 (m,1H), 1.41 (s, 9H). Mass spec.: 328.27 (MH)⁺.

3′-(hydroxymethyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile. Asolution of (3-bromo-5-(trifluoromethyl)phenyl)methanol (3.0 g, 11.8mmol), 4-cyanophenyl boronic acid (5.2 g, 35 mmol),tetrakis(triphenylphosphine) palladium(0) (2.7 g, 2.4 mmol), and aqueouspotassium hydroxide (41 mL, 1N, 41 mmol) in THF (80 mL) was degassedwith nitrogen for 10 minutes and then heated at 120° C. for 18 hours.The reaction was cooled to ambient temperature and poured into water(100 mL), then was diluted with ethyl acetate (100 mL) and the layerswere separated. The aqueous layer was extracted with ethyl acetate (2×20mL) and the combined organic layers were dried with MgSO₄ andevaporated. The residue was purified by chromatography on SiO₂ with agradient of ethyl acetate/hexanes of 5%-40%. The product3′-(hydroxymethyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile (1.66 g,51%) was obtained as a white solid. ¹H-NMR (CDCl_(3,) 400 MHz) δ7.65-7.80 (m, 7H), 4.85 (s, 2H), 1.90 (bs, 1H). Mass spec.:278.2 (M+H).

3′-(bromomethyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.N-bromosuccinimide (2.24 g, 12.6 mmol) was added to a 0° C. solution of3′-(hydroxymethyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile (1.66 g,6.0 mmol) and triphenylphosphine (3.14 g, 12.0 mmol) in THF (100 mL).The reaction was warmed to ambient temperature and stirred for 18 hours.The solvent was evaporated and the residue was purified bychromatography on SiO₂ with a gradient of ethyl acetate/hexanes of 5% to40%. The product3′-(bromomethyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile (1.30 g,64%) was obtained as a white solid. ¹H-NMR (CDCl_(3,) 400 MHz) δ7.65-7.80 (m, 7H), 4.56 (s, 2H).

tert-Butyl4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-(2,4-difluorophenyl)piperidine-1-carboxylate.tert-Butyl4-(2,4-difluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (220mg, 0.67 mmol) and 1-Bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene(450 mg, 1.41 mmol) were combined in tetrahydrofuran (2 mL) and cooledto 0° C. The reaction was treated with sodium tert-butoxide (75 mg,0.355 mmol) and stirred at 0° C. for 20 min. The reaction was treatedwith another aliquot of sodium tert-butoxide (75 mg, 0.355 mmol),allowed to warm to room temperature, and stirred for 30 min. Thereaction was diluted with 10% sodium bicarbonate and extracted withethyl acetate (2×). The organic layers were pooled together, washed withbrine (1×), dried over sodium sulfate, and concentrated. Columnchromatography on silica gel (0%→25% ethyl acetate/hexanes) gave 200 mg(50%). Mass spec.: 586.04 (MH)⁺ LC t_(r)=2.552 min. (Phenomenex-Luna4.6×50 mm S10, 10% MeOH/90% H₂O/0.1% TFA→90% MeOH/10% H₂O/0.1% TFAGradient Time=2 min, Flow rate=4 mL/min).

tert-butyl4-(2-bromo-4-fluorophenyl)-4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)piperidine-1-carboxylate.Potassium tert-butoxide (266 mg, 2.37 mmol) was added to a 0° C.solution of tert-butyl4-(2-bromo-4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate(460 mg, 1.18 mmol) and3′-(bromomethyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile (524 mg,1.54 mmol) in THF (10 mL) and was allowed to warm to ambient temperatureand stir for 24 hours. The solvent was evaporated and the residue waspurified by chromatography on SiO₂ with a gradient of ethylacetate/hexanes from 5% to 40%. The product tert-butyl4-(2-bromo-4-fluorophenyl)-4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)piperidine-1-carboxylate(520 mg, 68%) was isolated as a clear syrup. ¹H-NMR (CDCl_(3,) 400 MHz)δ 7.75 (d, J=8.3 Hz, 2H), 7.67 (s, 1H), 7.58 (d, J=8.3 Hz, 2H), 7.36 (m,3H), 7.22 (m, 1H), 6.99 (m, 1H), 4.49 (s, 2H), 3.94 (s, 2H), 3.57 (m,1H), 3.24 (m 1H), 2.48 (m, 2H), 2.05 (m, 2H), 1.42 (s, 9H). Mass spec.:647.2 (M+H).

tert-Butyl4-(3-bromophenyl)-4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)piperidine-1-carboxylate.¹H-NMR (CDCl₃, 500 MHz) δ ppm 7.75 (m, 2H), 7.67 (br s, 1H), 7.60 (m,2H), 7.48 (m, 1H), 7.41 (m, 2H), 7.31 (m, 1H), 7.28 (m, 1H), 7.18 (m,1H), 4.45 (m, 2H), 3.72 (m, 2H), 3.45 (m, 2H), 3.04 (m, 2H), 2.13 (m,2H), 1.85 (m, 2H), 1.42 (s, 9H). Mass spec.: 629.22 (MH)⁺.

tert-Butyl4-(3-chlorophenyl)-4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)piperidine-1-carboxylate.¹H-NMR (CDCl₃, 500 MHz) δ ppm 7.74 (m, 2H), 7.66 (s, 1H), 7.61 (s, 1H),7.44 (s, 1H), 7.37 (s, 1H), 7.18-7.29 (m, 4H), 7.17 (m, 1H), 4.47 (s,2H), 3.73 (m, 2H), 3.43 (s, 2H), 3.03 (m, 2H), 2.16 (m, 2H), 1.85 (m,2H), 1.42 (s, 9H). Mass spec.: 585.27 (MH)⁺.

tert-Butyl4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(3,4-difluorophenyl)piperidine-1-carboxylate.¹H-NMR (CDCl₃, 500 MHz) δ ppm 7.75 (m, 2H), 7.68 (s, 1H), 7.59 (m, 2H),7.42 (s, 1H), 7.38 (s, 1H), 7.01-7.19 (m, 3H), 4.47 (s, 2H), 3.69 (m,2H), 3.42 (s, 2H), 3.05 (m, 2H), 2.07 (m, 2H), 1.83 (m, 2H), 1.42 (s,9H).

tert-Butyl4-(4-bromophenyl)-4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)piperidine-1-carboxylate.¹H-NMR (CDCl₃, 500 MHz) δ ppm 7.78 (m, 2H), 7.68 (s, 1H), 7.59 (m, 2H),7.43 (m, 4H), 7.23 (m, 2H), 4.46 (s, 2H), 3.72 (m, 2H), 3.43 (s, 2H),3.02 (s, 2H), 2.14 (m, 2H), 1.83 (m, 2H), 1.42 (s, 9H). Mass spec.:653.06 (MNa)⁺.

tert-Butyl4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate.¹H-NMR (CDCl₃, 500 MHz) δ ppm 7.74 (m, 2H), 7.68 (s, 1H), 7.51-7.59 (m,4H), 7.36-7.45 (m, 4H), 4.46 (s, 2H), 3.70 (m, 2H), 3.47 (s, 2H),3.03-3.09 (m, 2H), 2.18 (m, 2H), 1.87-1.92 (m, 2H), 1.42 (s, 9H). Massspec.: 619.27 (MH)⁺.

tert-Butyl4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(3-methoxyphenyl)piperidine-1-carboxylate.¹H-NMR (CDCl₃, 500 MHz) δ ppm 7.74-7.76 (m, 2H), 7.67 (s, 1H), 7.59-7.62(m, 2H), 7.47 (s, 1H), 7.41 (s, 1H), 7.22-7.26 (m, 1H), 6.92-6.95 (m,1H), 6.90 (m, 1H), 6.73-6.76 (m, 1H), 4.45 (s, 2H), 3.70-3.78 (m, 2H),3.75 (s, 3H), 3.44 (s, 2H), 3.02 (m, 2H), 2.14-2.19 (m, 2H), 1.80-1.88(m, 2H), 1.41 (s, 9H). Mass spec.: 581.14 (MH)⁻.

tert-butyl4-(2-cyano-4-fluorophenyl)-4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)piperidine-1-carboxylate.A mixture of tert-butyl4-(2-bromo-4-fluorophenyl)-4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)piperidine-1-carboxylate(50 mg, 0.077 mmol), Zinc cyanide (13.60 mg, 0.1 16 mmol), andtetrakis(triphenylphosphine)palladium(0) (8.92 mg, 7.72 μmol) wereplaced in a sealable vessel and degassed with nitrogen for 5 min. Thevessel was then sealed and heated at 120° C. for 3 h. The reaction waspoured into brine (20 mL) and extracted with ethyl acetate (4×5 mL). Thecombined organic layers were dried (MgSO₄) and evaporated to dryness.The resulting residue was purified by chromatography on SiO₂ with aethyl acetate/hexanes gradient from 12% to 100%. The product tert-butyl4-(2-cyano-4-fluorophenyl)-4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)piperidine-1-carboxylate(39 mg, 85%) was obtained as a clear oil. ¹H-NMR (CDCl_(3,) 400 MHz) δ7.75 (d, J=8.7 Hz, 2H), 7.68 (s, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.45 (m,1H), 7.40 (s, 1H), 7.22-7.32 (m, 3H), 4.51 (s, 2H), 3.86 (s, 2H), 3.59(m, 1H), 3.28 (m, 2H), 2.47 (m, 2H), 2.10 (m, 2H), 1.42 (s, 9H). Massspec.: 594.3 (M+H).

tert-butyl4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(5-fluorobiphenyl-2-yl)piperidine-1-carboxylate.A mixture of tert-butyl4-(2-bromo-4-fluorophenyl)-4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)piperidine-1-carboxylate(100 mg, 0.15 mmol), phenyl boronic acid (19 mg, 0.15 mmol), potassiumcarbonate (43 mg, 0.31 mmol) andtetrakis(triphenylphosphine)palladium(0) (18 mg, 0. 15 mmol) were placedin a sealable vessel and degassed with nitrogen for 5 min. The vesselwas then sealed and heated at 120° C. for 3 h. The reaction was pouredinto brine (20 mL) and extracted with ethyl acetate (4×5 mL). Thecombined organic layers were dried (MgSO₄) and evaporated to dryness.The resulting residue was purified by chromatography on SiO₂ with aethyl acetate/hexanes gradient from 12% to 100%. The product tert-butyl4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(5-fluorobiphenyl-2-yl)piperidine-1-carboxylate(39 mg, 39%) was isolated as a clear oil. ¹H-NMR (CDCl_(3,) 400 MHz) δ7.68-7.76 (m, 3H), 7.55 (d, J=8.4 Hz, 2H), 7.44 (m, 3H), 7.18-7.28 (m,3H), 7.03 (m, 1H), 6.94 m, 2H), 6.67 (m, 1H), 4.52 (s, 2H), 3.52 (m,2H), 3.47 (s, 2H), 2.90 (m, 2H), 1.91 (m, 2H), 1.45 (m, 2H), 1.38 (s,9H). Mass spec.: 645.2 (M+H).

tert-Butyl4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(3-cyanophenyl)piperidine-1-carboxylate.A mixture of tert-Butyl4-(3-bromophenyl)-4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)piperidine-1-carboxylate(150 mg, 0.238 mmol), zinc cyanide (33.6 mg, 0.286 mmol), palladiumtetrakis triphenylphosphine (27.5 mg, 0.024 mmol), and dimethylformamide(1 mL) was charged to a conical vial and purged with nitrogen for 5minutes. The vial was sealed and heated at 120° C. for 2 hours and thenheld at room temperature overnight. The resulting mixture was filteredthrough a syringe tip filter and applied directly to a silica gelcolumn. Gradient elution with 5-40% ethyl acetate/hexanes afforded theproduct as a clear oil (83 mg, 61%). ¹H-NMR (CDCl₃, 500 MHz) δ ppm 7.76(m, 2H), 7.68 (s, 1H), 7.56-7.64 (m, 4H), 7.45-7.49 (m, 1H), 7.38-7.43(m, 2H), 7.34 (s, 1H), 3.69 (m, 2H), 3.45 (s, 2H), 3.05 (m, 2H), 2.10(m, 2H), 1.88 (m, 2H), 1.42 (s, 9H). Mass spec.: 576.17 (MH)⁺.

tert-Butyl4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(4-cyanophenyl)piperidine-1-carboxylate.¹H-NMR (CDCl₃, 500 MHz) δ ppm 7.77 (m, 2H), 7.68 (s, 1H), 7.58-7.63 (m,4H), 7.46 (m, 2H), 7.43 (s, 1H), 7.35 (s, 1H), 4.46 (s, 2H), 3.68 (m,2H), 3.47 (s, 2H), 3.05 (m, 2H), 2.17 (m, 2H), 1.85-1.92 (m, 2H), 1.42(s, 9H). Mass spec.: 576.16 (MH)⁺.

tert-Butyl4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(4-(furan-2-yl)phenyl)piperidine-1-carboxylate.A solution of tert-butyl4-(4-bromophenyl)-4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)piperidine-1-carboxylate(175 mg, 0.278 mmol), 2-(tributylstannyl)furan (109 mg, 0.306 mmol), andtoluene (1.5 ml) in a conical reaction vial was purged with nitrogen for10 minutes. Palladium tetrakistriphenylphosphine (321 mg, 0.278 mmol)was added. The vial was sealed and heated 120° C. overnight. Theresulting mixture was cooled to room temperature and partitioned betweenethyl acetate and brine. The organics were dried over sodium sulfate,filtered, and concentrated to a light amber oil. Silica gel columnchromatography (5-40% ethyl acetate/hexanes) afforded the product as acolorless oil (130 mg, 72%). ¹H-NMR (CDCl₃, 500 MHz) δ ppm 7.64 (s, 1H),7.57-7.60 (m, 4H), 7.49 (m, 3H), 7.41 (s, 1H), 7.32-7.37 (m, 3H), 6.61(m, 1H), 6.51 (m, 1H), 4.47 (s, 2H), 3.74 (br m, 2H), 3.46 (s, 2H), 3.04(m, 2H), 2.22 (m, 2H), 1.83 (m, 2H), 1.42 (s, 9H). Mass spec.: 617.25(MH)⁺.

(3-Nitro-5-(trifluoromethyl)phenyl)methanol.3-Nitro-5-(trifluoromethyl)benzoic acid (5.0 g, 21.2 mmol) was combinedwith tetrahydrofuran (43 mL) and cooled to 0° C. To this solution wasadded a 1 M borane tetrahydrofuran complex (42 mL, 42 mmol) cautiouslyover 15 min and the reaction mixture allowed to warm to room temperatureovernight. The mixture was cooled to 0° C., treated with excess methanoland concentrated in vacuo to afford 4.0 g (85%) which was used withoutfurther purification. ¹H-NMR (CDCl_(3,) 300 MHz) δ 8.39 (s, 1H), 8.35(s, 1H), 7.94 (s, 1H), 4.87 (s, 2H).

(3-Amino-5-(trifluoromethyl)phenyl)methanol.(3-Nitro-5-(trifluoromethyl)phenyl)methanol (2.6 g, 11.6 mmol) inmethanol (30 mL) was flushed with nitrogen, and treated with palladium(10% on charcoal, 260 mg). The flask was flushed with hydrogen andallowed to stir under an atmosphere of hydrogen overnight. The reactionwas flushed with nitrogen, filtered through celite, and concentrated.Column chromatography on silica gel (50% ethyl acetate/hexanes) afforded1.9 g (85%). ¹H-NMR (CDCl_(3,) 500 MHz) δ 6.95 (s, 1H), 6.80 (s, 1H),6.79 (s, 1H), 4.61 (s, 2H). Mass spec.: 192.15 (MH)⁺.

(3-Bromo-5-(trifluoromethyl)phenyl)methanol.(3-Amino-5-(trifluoromethyl)phenyl)methanol (1.6 g, 8.4 mmol) in dryacetonitrile (10 mL) was added dropwise to a solution of copper (II)bromide (2.24 g, 10.0 mmol) and tert-butyl nitrite (1.48 mL, 12.0 mmol)in acetonitrile (20 mL) at 65° C. After stirring for 30 min at 65° C.,the reaction mixture was cooled to room temperature, poured into a 1 Nhydrochloric acid solution, and extracted with ethyl acetate (2×). Theorganic layers were pooled together, washed with brine (2×), dried oversodium sulfate, and concentrated. Column chromatography on silica gel(20% ethyl acetate/hexanes) afforded 1.48 g (69%). ¹H-NMR (CDCl_(3,) 500MHz) δ 7.71 (s, 1H), 7.68 (s, 1H), 7.55 (s, 1H), 4.75 (s, 2H).

1-Bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene.(3-Bromo-5-(trifluoromethyl)phenyl)methanol (1.6 g, 6.3 mmol) andtriphenylphosphine (3.3 g, 12.6 mmol) were combined in tetrahydrofuran(30 mL) and cooled to 0° C. N-Bromosuccinimide (2.4 g, 13.2 mmol) wasintroduced in portions and the reaction allowed to warm to roomtemperature. After 16 h, the reaction mixture was diluted with ethylacetate, washed with concentrated sodium bicarbonate (2×), brine (2×),dried over sodium sulfate, and concentrated. Column chromatography onsilica gel (100% hexanes) gave 1.53 g (76%) as a light brown oil. ¹H-NMR(CDCl_(3,) 500 MHz) δ 7.73 (s, 1H), 7.70 (s, 1H), 7.58 (s, 1H), 4.44 (s,2H).

tert-Butyl4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.1-Bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (1.0 g, 3.14 mmol)and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.70g, 2.4 mmol) were combined in dimethylformamide (8 mL) and cooled to 0°C. The reaction was treated with sodium hydride (115 mg, 4.8 mmol),stirred at 0° C. for 1 h, and at room temperature for 30 min. Thereaction mixture was diluted with water and extracted with ethyl acetate(2×). The organic layers were pooled together, washed with brine (2×),dried over sodium sulfate, and concentrated. Column chromatography onsilica gel (20% ethyl acetate/hexanes) gave 1.6 g (96%). ¹H-NMR(CDCl_(3,) 500 MHz) δ 7.61 (s, 1H), 7.39 (s, 1H), 7.34-7.37 (m, 4H),7.25-7.28 (m, 2H), 4.35 (s, 2H), 3.75-3.77 (m, 2H), 3.41 (s, 2H),3.01-3.06 (m, 2H), 2.19-2.22 (m, 2H), 1.83-1.89 (m, 2H), 1.44 (s, 9H).Mass spec.: 530.21 (MH)⁺.

tert-Butyl4-phenyl-4-((3-(tributylstannyl)-5-(trifluoromethyl)benzyloxy)methyl)piperidine-1-carboxylate.To a solution of tert-butyl4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate(5.5 g, 10.4 mmol) in tetrahydrofuran (60 mL) at −78° C. was addedn-butyllithium (1.6 M in hexane, 7.48 mL, 12.0 mmol) dropwise. Thereaction was stirred at −78° C. for 20 min and treated with tributyltinchloride (3.25 mL, 12.0 mmol). The reaction was allowed to graduallywarm to room temperature in the dewar over several hours. The reactionwas poured into pentane, washed with water (2×), then brine, dried overmagnesium sulfate, and concentrated. Column chromatography (5%→8% ethylacetate/hexanes) gave 6.1 g (79%) as a colorless oil. ¹H-NMR (CDCl₃, 500MHz) δ 7.56 (s, 1H), 7.44 (s, 1H), 7.37 (m, 5H), 7.24 (m, 1H), 4.38 (s,2H), 3.74 (m, 2H), 3.43 (s, 2H), 3.06 (m, 2H), 2.20 (m, 2H), 1.90 (m,2H), 1.54 (m, 6H), 1.44 (s, 9H), 1.34 (m, 6H), 1.09 (m, 6H), 0.90 (m,9H); ¹³C NMR (126 MHz, CDCl₃) δ ppm 155.1143.6, 142.9, 138.4, 138.3,131.7 (q, J=3.8 Hz), 130.0 (q, J=32 Hz), 128.5, 127.3, 126.5, 124.6 (q,J=273 Hz), 123.7 (q, J=3.8 Hz), 79.6, 79.3, 72.9, 41.7, 40.2 (br), 32.1,29.1, 28.6, 27.3, 13.7, 9.8.

(3-Chloro-5-(trifluoromethyl)phenyl)methanol.(3-Amino-5-(trifluoromethyl)phenyl)methanol (1.0 g, 5.23 mmol) in dryacetonitrile (6 mL) was added dropwise to a solution of copper (II)chloride (0.83 g, 6.2 mmol) and tert-butyl nitrite (0.9 mL, 7.5 mmol) inacetonitrile (6 mL) at 65° C. After 30 min at 65° C., the reactionmixture was cooled to room temperature, poured into a 1 N hydrochloricacid solution, and extracted with ethyl acetate (2×). The organic layerswere pooled together, washed with brine (2×), dried over sodium sulfate,and concentrated. Column chromatography on silica gel (30% ethylacetate/hexanes) afforded 0.8 g (73%). ¹H-NMR (CDCl₃, 500 MHz) δ 7.54(s, 1H), 7.52 (s, 1H), 7.50 (s, 1H), 4.74 (s, 2H).

1-(Bromomethyl)-3-chloro-5-(trifluoromethyl)benzene.(3-Chloro-5-(trifluoromethyl)phenyl)methanol (0.78 g, 3.7 mmol) andtriphenylphosphine (1.94 g, 7.4 mmol) were combined in tetrahydrofuran(18 mL) and cooled to 0° C. N-Bromosuccinimide (1.4 g, 7.8 mmol) wasintroduced in portions and the reaction allowed to warm to roomtemperature. After 16 h, the reaction mixture was diluted with ethylacetate, washed with concentrated sodium bicarbonate (2×), brine (2×),dried over sodium sulfate, and concentrated. Column chromatography onsilica gel (10% ethyl acetate/hexanes) gave 0.94 g (92%). ¹H-NMR(CDCl_(3,) 300 MHz) δ 7.55 (s, 1H), 7.52 (s, 1H), 7.51 (s, 1H), 4.42 (s,2H).

tert-Butyl4-((3-chloro-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.1-(Bromomethyl)-3-chloro-5-(trifluoromethyl)benzene (0.94 g, 3.4 mmol)and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (1.0g, 3.4 mmol) were combined in dimethylformamide (8 mL) and cooled to 0°C. The reaction was treated with sodium hydride (95 mg, 3.7 mmol),stirred at 0° C. for 1 h, and at room temperature overnight. Thereaction mixture was diluted with water and extracted with ethyl acetate(2×). The organic layers were pooled together, washed with brine (2×),dried over sodium sulfate, and concentrated. Column chromatography onsilica gel (20% ethyl acetate/hexanes) gave 0.78 g (52%). LC/MS (HPLCmethod 3): t_(R)=3.65 min, 484.20(MH)⁺.

1-(Bromomethyl)-3-nitro-5-(trifluoromethyl)benzene.(3-Nitro-5-(trifluoromethyl)phenyl)methanol (0.5 g, 2.26 mmol) andtriphenylphosphine (1.19 g, 4.5 mmol) were combined in tetrahydrofuran(15 mL) and cooled to 0° C. N-Bromosuccinimide (0.8 g, 4.8 mmol) wasintroduced in portions and the reaction allowed to warm to roomtemperature. After 16 h, the reaction mixture was diluted with ethylacetate, washed with concentrated sodium bicarbonate (2×), brine (2×),dried over sodium sulfate, and concentrated. Column chromatography onsilica gel (10% ethyl acetate/hexanes) gave 0.58 g (91%). ¹H-NMR(CDCl_(3,) 500 MHz) δ 8.42 (s, 1H), 8.39 (s, 1H), 7.97 (s, 1H), 4.90 (s,2H).

tert-Butyl4-((3-nitro-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.1-(Bromomethyl)-3-nitro-5-(trifluoromethyl)benzene (150 mg, 0.53 mmol)and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (142mg, 0.49 mmol) were combined in dimethylformamide (3 mL) and cooled to0° C. The reaction was treated with sodium hydride (14 mg, 0.53 mmol),stirred at 0° C. for 1 h, and at room temperature overnight. Thereaction mixture was diluted with water and extracted with ethyl acetate(2×). The organic layers were pooled together, washed with brine (2×),dried over sodium sulfate, and concentrated. Column chromatography onsilica gel (10% ethyl acetate/hexanes) gave 138 mg (53%). LC/MS (HPLCmethod 3): t_(R)=3.42 min, 495.18(MH)⁺.

tert-Butyl4-((3-amino-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.tert-Butyl4-((3-nitro-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate(118 mg, 0.24 mmol) in methanol (2.5 mL) was flushed with nitrogen, andtreated with palladium (10% on charcoal, 12 mg). The flask was flushedwith hydrogen and allowed to stir under an atmosphere of hydrogenovernight. The reaction was flushed with nitrogen, filtered throughcelite, and concentrated to afford 90 mg (80%). LC/MS (HPLC method 3):t_(R)=3.10 min, 465.22(MH)⁺.

tert-Butyl4-phenyl-4-((3-(2,2,2-trifluoroacetamido)-5-(trifluoromethyl)benzyloxy)methyl)piperidine-1-carboxylate.tert-Butyl4-((3-amino-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate(90 mg, 0.19 mmol) and triethylamine (52.0 μL, 0.37 mmol) were combinedin methylene chloride (2 mL) and cooled to 0° C. The reaction wastreated with trifluoroacetic anhydride (33.0 μL, 0.23 mmol), stirred at0° C. for 2 h, and at room temperature overnight. The reaction wascooled to 0° C., quenched by addition of a few drops of methanol andconcentrated. Flash chromatography on silica gel (40% ethylacetate/hexanes) gave 106 mg (98%). LC/MS (HPLC method 3): t_(R)=3.38min, 561.18(MH)⁺.

tert-Butyl4-phenyl-4-((3-(trifluoromethyl)-5-(5-(trifluoromethyl)-1H-tetrazol-1-yl)benzyloxy)methyl)piperidine-1-carboxylate.tert-Butyl4-phenyl-4-((3-(2,2,2-trifluoroacetamido)-5-(trifluoromethyl)benzyloxy)methyl)piperidine-1-carboxylate(100 mg, 0. 18 mmol) in carbon tetrachloride (3 mL) was treated withtriphenylphosphine (117 mg, 0.45 mmol) and heated at reflux overnight.After cooling to room temperature, the reaction was concentrated and theresidue dissolved in dimethylformamide (2 mL). The mixture was treatedwith sodium azide (25 mg, 0.37 mmol) and stirred at room temperature for5 h. The solvents were evaporated and the crude product purified byflash chromatography on silica gel (30% ethyl acetate/hexanes) to afford46 mg (45%). ¹H-NMR (CDCl_(3,) 500 MHz) δ 7.61 (s, 1H), 7.59 (s, 1H),7.30-7.32 (m, 2H), 7.23-7.26 (m, 2H), 7.12 (s, 1H), 7.05-7.08 (m, 1H),4.51 (s, 2H), 3.74 (m, 2H), 3.46 (s, 2H), 2.99-3.03 (m, 2H), 2.21-2.24(m, 2H), 1.79-1.84 (m, 2H), 1.42 (s, 9H). Mass spec.: 608.16 (MNa)⁺.

Methyl 5-formyl-2-methoxybenzoate. 5-Formyl salicylic acid (2.0 g, 12.0mmol), methyl iodide (1.5 mL, 25 mmol) and potassium carbonate (3.06 g,22.2 mmol) were combined in dimethylformamide (15 mL). After stirring atroom temperature for 16 h, the solvent was removed in vacuo and thecrude product dissolved in ethyl acetate, washed with water (2×), brine(2×), dried over sodium sulfate, concentrated, and purified by columnchromatography to afford 1.85 g (79%). ¹H-NMR (CDCl_(3,) 500 MHz) δ 9.91(s, 1H), 8.31 (d, J=2.1 Hz, 1H), 8.02 (dd, J=8.5, 2.5 Hz, 1H), 7.11 (d,J=8.6 Hz, 1H), 3.99 (s, 3H), 3.91 (s, 3H). Mass spec.: 195.05 (MH)⁺.

Methyl 5-((hydroxyimino)methyl)-2-methoxybenzoate. Methyl5-formyl-2-methoxybenzoate 1.0 g, 5.15 mmol), hydroxylaminehydrochloride (1.8 g, 25.75 mmol) and sodium acetate (2.1 g, 25.75 mmol)were combined in a ethanol/water mixture (1:1, 40 mL) and stirred at 50°C. for 1 h. After cooling to room temperature, the reaction mixture waspoured in to ice water and extracted with methylene chloride (2×). Thecombined organic layers were washed with brine (2×), dried over sodiumsulfate and concentrated to afford 1.04 g (97%) which was used withoutpurification. LC/MS (HPLC method 3): t_(R)=1.63 min, 210.06(MH)⁺.

Methyl 5-cyano-2-methoxybenzoate. Methyl5-((hydroxyimino)methyl)-2-methoxybenzoate (1.04 g, 4.94 mmol) wasdissolved in methylene chloride (25 mL) and cooled to 0° C. The reactionwas treated with thionyl chloride (0.59 mL, 8.1 mmol) and stirred at 0°C. for 2 h. After warming to room temperature, the reaction was dilutedwith methylene chloride, washed with saturated sodium bicarbonate (2×),brine (2×), dried over sodium sulfate, and concentrated to afford 0.87 g(92%) which was used without further purification. ¹H-NMR (CDCl_(3,) 500MHz) δ 8.09 (d, J=2.1 Hz, 1H), 7.75 (dd, J=8.9, 2.1 Hz, 1H), 7.05 (d,J=8.9 Hz, 1H), 3.96 (s, 3H), 3.90 (s, 3H). Mass spec.: 192.02 (MH)⁺.

Methyl 2-methoxy-5-(1H-tetrazol-5-yl)benzoate. A stirred solution ofmethyl 5-cyano-2-methoxybenzoate (0.87 g, 4.5 mmol) in toluene (4 mL)was treated with azidotrimethyltin (1.85 g, 9.0 mmol) and heated atreflux overnight. After cooling to room temperature, the solvents wereevaporated. The crude product was dissolved in ethyl acetate, washedwith brine (2×), dried over sodium sulfate, and concentrated. Columnchromatography on silica gel (5% methanol/methylene chloride) afforded0.78 g (75%). LC/MS (HPLC method 3): t_(R)=1.66 min, 235.05(MH)⁻.

Methyl 2-methoxy-5-(2-methyl-2H-tetrazol-5-yl)benzoate. Methyl2-methoxy-5-(1H-tetrazol-5-yl)benzoate (0.78 g, 3.33 mmol) methyl iodide(0.21 mL, 3.33 mmol) and potassium carbonate (0.46 g, 3.33 mmol) werecombined in acetone (8 mL) and heated at reflux overnight. After coolingto room temperature, the mixture was filtered and concentrated. Flashchromatography on silica gel afforded 170 mg (21%). LC/MS(HPLC method3): t_(R)=2.01 min, 249.09(MH)⁺

(2-Methoxy-5-(2-methyl-2H-tetrazol-5-yl)phenyl)methanol. Methyl2-methoxy-5-(2-methyl-2H-tetrazol-5-yl)benzoate (130 mg, 0.52 mmol) wasdissolved in methylene chloride (2 mL), cooled to −78° C. and treatedwith diisobutylaluminum hydride (1 M in methylene chloride, 1.5 mL, 1.5mmol). After stirring at −78° C. for 1 h the reaction was quenched by afew drops of methanol (until no bubbling was observed) followed byaddition of excess saturated sodium potassium tartarate (2 mL). Thereaction was stirred at room temperature overnight, the layers wereseparated and the organic layer washed with brine (2×), dried oversodium sulfate and concentrated to afford 100 mg (86%). LC/MS (HPLCmethod 3): t_(R)=1.68 min, 221.11 (MH)⁺

5-(3-(Bromomethyl)-4-methoxyphenyl)-2-methyl-2H-tetrazole.(2-Methoxy-5-(2-methyl-2H-tetrazol-5-yl)phenyl)methanol (100 mg, 0.45mmol) and triphenylphosphine (238 mg, 0.9 mmol) were combined inmethylene chloride (3 mL) and cooled to 0° C. N-Bromosuccinimide (170mg, 0.95 mmol) was introduced in portions and the reaction allowed towarm to room temperature. After 16 h, the reaction mixture was dilutedwith methylene chloride and washed with concentrated sodium bicarbonate(2×), brine (2×), dried over sodium sulfate, and concentrated. Columnchromatography on silica gel (30% ethyl acetate/hexanes) gave 80 mg(63%) of the desired material. LC/MS (HPLC method 3): t_(R)=2.69 min,285.02(MH)⁺.

tert-Butyl4-((2-methoxy-5-(2-methyl-2H-tetrazol-5-yl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.5-(3-(Bromomethyl)-4-methoxyphenyl)-2-methyl-2H-tetrazole (35.0 mg, 0.12 mmol) and tert-butyl4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (40.0 mg, 0. 14 mmol)were combined in dimethylformamide (1 mL) and cooled to 0° C. Thereaction was treated with sodium hydride (3.2 mg, 0.14 mmol), stirred at0° C. for 1 h, and at room temperature overnight. The solvents wereremoved in vacuo and the crude product purified by column chromatographyon silica gel (30% ethyl acetate/hexanes) to afford 30 mg (50%). LC/MS(HPLC method 3): t_(R)=3.29 min, 494.25(MH)⁺.

Methyl 5-formyl-2-methoxybenzoate. 5-Formyl salicylic acid (2.0 g, 12.0mmol), methyl iodide (1.5 mL, 25 mmol) and potassium carbonate (3.06 g,22.2 mmol) were combined in dimethylformamide (15 mL). After stirring atroom temperature for 16 h, the solvent was removed in vacuo and thecrude product dissolved in ethyl acetate, washed with water (2×), brine(2×), dried over sodium sulfate, concentrated, and purified by columnchromatography to afford 1.85 g (79%). ¹H-NMR (CDCl_(3,) 500 MHz) δ 9.91(s, 1H), 8.31 (d, J=2.1 Hz, 1H), 8.02 (dd, J=8.5, 2.5 Hz, 1H), 7.11 (d,J=8.6 Hz, 1H), 3.99 (s, 3H), 3.91 (s, 3H). Mass spec.: 195.05 (MH)⁺.

Methyl 5-((hydroxyimino)methyl)-2-methoxybenzoate. Methyl5-formyl-2-methoxybenzoate 1.0 g, 5.15 mmol), hydroxylaminehydrochloride (1.8 g, 25.75 mmol) and sodium acetate (2.1 g, 25.75 mmol)were combined in a ethanol/water mixture (1:1, 40 mL) and stirred at 50°C. for 1 h. After cooling to room temperature, the reaction mixture waspoured in to ice water and extracted with methylene chloride (2×). Thecombined organic layers were washed with brine (2×), dried over sodiumsulfate and concentrated to afford 1.04 g (97%) which was used withoutpurification. LC/MS (HPLC method 3): t_(R)=1.63 min, 210.06(MH)⁺.

Methyl 5-cyano-2-methoxybenzoate. Methyl5-((hydroxyimino)methyl)-2-methoxybenzoate (1.04 g, 4.94 mmol) wasdissolved in methylene chloride (25 mL) and cooled to 0° C. The reactionwas treated with thionyl chloride (0.59 mL, 8.1 mmol) and stirred at 0°C. for 2 h. After warming to room temperature, the reaction was dilutedwith methylene chloride, washed with saturated sodium bicarbonate (2×),brine (2×), dried over sodium sulfate, and concentrated to afford 0.87 g(92%) which was used without further purification. ¹H-NMR (CDCl_(3,) 500MHz) δ 8.09 (d, J=2.1 Hz, 1H), 7.75 (dd, J=8.9, 2.1 Hz, 1H), 7.05 (d,J=8.9 Hz, 1H), 3.96 (s, 3H), 3.90 (s, 3H). Mass spec.: 192.02 (MH)⁺.

Methyl 2-methoxy-5-(1H-tetrazol-5-yl)benzoate. A stirred solution ofmethyl 5-cyano-2-methoxybenzoate (0.87 g, 4.5 mmol) in toluene (4 mL)was treated with azidotrimethyltin (1.85 g, 9.0 mmol) and heated atreflux overnight. After cooling to room temperature, the solvents wereevaporated. The crude product was dissolved in ethyl acetate, washedwith brine (2×), dried over sodium sulfate, and concentrated. Columnchromatography on silica gel (5% methanol/methylene chloride) afforded0.78 g (75%). LC/MS (HPLC method 3): t_(R)=1.66 min, 235.05(MH)⁻.

Methyl 2-methoxy-5-(2-methyl-2H-tetrazol-5-yl)benzoate. Methyl2-methoxy-5-(1H-tetrazol-5-yl)benzoate (0.78 g, 3.33 mmol) methyl iodide(0.21 mL, 3.33 mmol) and potassium carbonate (0.46 g, 3.33 mmol) werecombined in acetone (8 mL) and heated at reflux overnight. After coolingto room temperature, the mixture was filtered and concentrated. Flashchromatography on silica gel afforded 170 mg (21%). LC/MS(HPLC method3): t_(R)=2.01 min, 249.09(MH)⁺

(2-Methoxy-5-(2-methyl-2H-tetrazol-5-yl)phenyl)methanol. Methyl2-methoxy-5-(2-methyl-2H-tetrazol-5-yl)benzoate (130 mg, 0.52 mmol) wasdissolved in methylene chloride (2 mL), cooled to −78° C. and treatedwith diisobutylaluminum hydride (1 M in methylene chloride, 1.5 mL, 1.5mmol). After stirring at −78° C. for 1 h the reaction was quenched by afew drops of methanol (until no bubbling was observed) followed byaddition of excess saturated sodium potassium tartarate (2 mL). Thereaction was stirred at room temperature overnight, the layers wereseparated and the organic layer washed with brine (2×), dried oversodium sulfate and concentrated to afford 100 mg (86%). LC/MS (HPLCmethod 3): t_(R)=1.68 min, 221.11 (MH)⁺

5-(3-(Bromomethyl)-4-methoxyphenyl)-2-methyl-2H-tetrazole.(2-Methoxy-5-(2-methyl-2H-tetrazol-5-yl)phenyl)methanol (100 mg, 0.45mmol) and triphenylphosphine (238 mg, 0.9 mmol) were combined inmethylene chloride (3 mL) and cooled to 0° C. N-Bromosuccinimide (170mg, 0.95 mmol) was introduced in portions and the reaction allowed towarm to room temperature. After 16 h, the reaction mixture was dilutedwith methylene chloride and washed with concentrated sodium bicarbonate(2×), brine (2×), dried over sodium sulfate, and concentrated. Columnchromatography on silica gel (30% ethyl acetate/hexanes) gave 80 mg(63%) of the desired material. LC/MS (HPLC method 3): t_(R)=2.69 min,285.02(MH)⁺.

tert-Butyl4-((2-methoxy-5-(2-methyl-2H-tetrazol-5-yl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.5-(3-(Bromomethyl)-4-methoxyphenyl)-2-methyl-2H-tetrazole (35.0 mg, 0.12mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate(40.0 mg, 0.14 mmol) were combined in dimethylformamide (1 mL) andcooled to 0° C. The reaction was treated with sodium hydride (3.2 mg,0.14 mmol), stirred at 0° C. for 1 h, and at room temperature overnight.The solvents were removed in vacuo and the crude product purified bycolumn chromatography on silica gel (30% ethyl acetate/hexanes) toafford 30 mg (50%). LC/MS (HPLC method 3): t_(R)=3.29 min, 494.25(MH)⁺.

Methyl 5-formyl-2-methoxybenzoate. 5-Formyl salicylic acid (2.0 g, 12.0mmol), methyl iodide (1.5 mL, 25 mmol) and potassium carbonate (3.06 g,22.2 mmol) were combined in dimethylformamide (15 mL). After stirring atroom temperature for 16 h, the solvent was removed in vacuo and thecrude product dissolved in ethyl acetate, washed with water (2×), brine(2×), dried over sodium sulfate, concentrated, and purified by columnchromatography to afford 1.85 g (79%). ¹H-NMR (CDCl_(3,) 500 MHz) δ 9.91(s, 1H), 8.31 (d, J=2.1 Hz, 1H), 8.02 (dd, J=8.5, 2.5 Hz, 1H), 7.11 (d,J=8.6 Hz, 1H), 3.99 (s, 3H), 3.91 (s, 3H). Mass spec.: 195.05 (MH)⁺.

Methyl 5-((hydroxyimino)methyl)-2-methoxybenzoate. Methyl5-formyl-2-methoxybenzoate 1.0 g, 5.15 mmol), hydroxylaminehydrochloride (1.8 g, 25.75 mmol) and sodium acetate (2.1 g, 25.75 mmol)were combined in a ethanol/water mixture (1:1, 40 mL) and stirred at 50°C. for 1 h. After cooling to room temperature, the reaction mixture waspoured in to ice water and extracted with methylene chloride (2×). Thecombined organic layers were washed with brine (2×), dried over sodiumsulfate and concentrated to afford 1.04 g (97%) which was used withoutpurification. LC/MS (HPLC method 3): t_(R)=1.63 min, 210.06(MH)⁺.

Methyl 5-cyano-2-methoxybenzoate. Methyl5-((hydroxyimino)methyl)-2-methoxybenzoate (1.04 g, 4.94 mmol) wasdissolved in methylene chloride (25 mL) and cooled to 0° C. The reactionwas treated with thionyl chloride (0.59 mL, 8.1 mmol) and stirred at 0°C. for 2 h. After warming to room temperature, the reaction was dilutedwith methylene chloride, washed with saturated sodium bicarbonate (2×),brine (2×), dried over sodium sulfate, and concentrated to afford 0.87 g(92%) which was used without further purification. ¹H-NMR (CDCl_(3,) 500MHz) δ 8.09 (d, J=2.1 Hz, 1H), 7.75 (dd, J=8.9, 2.1 Hz, 1H), 7.05 (d,J=8.9 Hz, 1H), 3.96 (s, 3H), 3.90 (s, 3H). Mass spec.: 192.02 (MH)⁺.

Methyl 2-methoxy-5-(1H-tetrazol-5-yl)benzoate. A stirred solution ofmethyl 5-cyano-2-methoxybenzoate (0.87 g, 4.5 mmol) in toluene (4 mL)was treated with azidotrimethyltin (1.85 g, 9.0 mmol) and heated atreflux overnight. After cooling to room temperature, the solvents wereevaporated. The crude product was dissolved in ethyl acetate, washedwith brine (2×), dried over sodium sulfate, and concentrated. Columnchromatography on silica gel (5% methanol/methylene chloride) afforded0.78 g (75%). LC/MS (HPLC method 3): t_(R)=1.66 min, 235.05(MH)⁻.

Methyl 2-methoxy-5-(2-methyl-2H-tetrazol-5-yl)benzoate. Methyl2-methoxy-5-(1H-tetrazol-5-yl)benzoate (0.78 g, 3.33 mmol) methyl iodide(0.21 mL, 3.33 mmol) and potassium carbonate (0.46 g, 3.33 mmol) werecombined in acetone (8 mL) and heated at reflux overnight. After coolingto room temperature, the mixture was filtered and concentrated. Flashchromatography on silica gel afforded 170 mg (21%). LC/MS(HPLC method3): t_(R)=2.01 min, 249.09(MH)⁺

(2-Methoxy-5-(2-methyl-2H-tetrazol-5-yl)phenyl)methanol. Methyl2-methoxy-5-(2-methyl-2H-tetrazol-5-yl)benzoate (130 mg, 0.52 mmol) wasdissolved in methylene chloride (2 mL), cooled to −78° C. and treatedwith diisobutylaluminum hydride (1 M in methylene chloride, 1.5 mL, 1.5mmol). After stirring at −78° C. for 1 h the reaction was quenched by afew drops of methanol (until no bubbling was observed) followed byaddition of excess saturated sodium potassium tartarate (2 mL). Thereaction was stirred at room temperature overnight, the layers wereseparated and the organic layer washed with brine (2×), dried oversodium sulfate and concentrated to afford 100 mg (86%). LC/MS (HPLCmethod 3): t_(R)=1.68 min, 221.11 (MH)⁺

5-(3-(Bromomethyl)-4-methoxyphenyl)-2-methyl-2H-tetrazole.(2-Methoxy-5-(2-methyl-2H-tetrazol-5-yl)phenyl)methanol (100 mg, 0.45mmol) and triphenylphosphine (238 mg, 0.9 mmol) were combined inmethylene chloride (3 mL) and cooled to 0° C. N-Bromosuccinimide (170mg, 0.95 mmol) was introduced in portions and the reaction allowed towarm to room temperature. After 16 h, the reaction mixture was dilutedwith methylene chloride and washed with concentrated sodium bicarbonate(2×), brine (2×), dried over sodium sulfate, and concentrated. Columnchromatography on silica gel (30% ethyl acetate/hexanes) gave 80 mg(63%) of the desired material. LC/MS (HPLC method 3): t_(R)=2.69 min,285.02(MH)⁺.

tert-Butyl4-((2-methoxy-5-(2-methyl-2H-tetrazol-5-yl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.5-(3-(Bromomethyl)-4-methoxyphenyl)-2-methyl-2H-tetrazole (35.0 mg, 0.12mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate(40.0 mg, 0.14 mmol) were combined in dimethylformamide (1 mL) andcooled to 0° C. The reaction was treated with sodium hydride (3.2 mg,0.14 mmol), stirred at 0° C. for 1 h, and at room temperature overnight.The solvents were removed in vacuo and the crude product purified bycolumn chromatography on silica gel (30% ethyl acetate/hexanes) toafford 30 mg (50%). LC/MS (HPLC method 3): t_(R)=3.29 min, 494.25(MH)⁺.

3-(Hydroxymethyl)-5-(trifluoromethyl)benzonitrile.(3-Bromo-5-(trifluoromethyl)phenyl)methanol (1.4 g, 5.5 mmol),tetrakis(triphenylphosphine) palladium(0) (0.64, 0.55 mmol) and zinccyanide (388 mg, 3.31 mmol) were combined in dimethylformamide (6 mL).The reaction mixture degassed repeatedly using the freeze-thaw method.After warming to room temperature, the reaction was heated at 90° C. for1 h, cooled to room temperature and concentrated. The crude product wasdissolved in ethyl acetate, washed with water (2×), 1 N hydrochloricacid (2×), brine (2×), dried over sodium sulfate, and concentrated.Flash chromatography on silica gel gave 0.37 g (33%). LC/MS (HPLC method3): t_(R)=2.06 min, 202.02(MH)⁺.

3-(Bromomethyl)-5-(trifluoromethyl)benzonitrile.3-(Hydroxymethyl)-5-(trifluoromethyl)benzonitrile (0.33 mg, 1.64 mmol)and triphenylphosphine (0.86 g, 3.28 mmol) were combined in methylenechloride (6 mL) and cooled to 0° C. N-Bromosuccinimide (0.61 mg, 3.43mmol) was introduced in portions and the reaction allowed to warm toroom temperature. After 16 h, the reaction mixture was diluted withmethylene chloride, washed with concentrated sodium bicarbonate (2×),brine (2×), dried over sodium sulfate, and concentrated. Columnchromatography on silica gel (20% ethyl acetate/hexanes) gave 0.36 g(83%). ¹H-NMR (CDCl_(3,) 500 MHz) δ 7.97 (s, 2H), 7.84 (s, 1H), 4.50 (s,2H).

tert-Butyl4-((3-(1H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.3-(Bromomethyl)-5-(trifluoromethyl)benzonitrile (0.35 g, 1.32 mmol) andtert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.35 g,1.2 mmol) were combined in tetrahydrofuran (4 mL) and cooled to 0° C.The reaction was treated with sodium hydride (33.2 mg, 1.32 mmol),stirred at 0° C. for 1 h, and at room temperature overnight. Thereaction mixture was diluted with water and extracted with ethyl acetate(2×). The organic layers were pooled together, washed with brine (2×),dried over sodium sulfate, and concentrated to afford a crude productwhich was dissolved in toluene (2.0), treated with azidotrimethytin (104mg, 0.5 mmol) and heated at reflux overnight. After cooling to roomtemperature, the solvents were evaporated. The crude mixture wasdissolved in methylene chloride, washed with water (2×), brine (2×),dried over sodium sulfate and concentrated. Flash chromatography onsilica gel afforded 102 mg (12%, 2 steps). LC/MS (HPLC method 3):t_(R)=3.25 min, 518.29(MH)⁺.

tert-Butyl4-((3-(1-methyl-1H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylateand tert-Butyl4-((3-(2-methyl-2H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.tert-Butyl4-((3-(1H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate(80 mg, 0.15 mmol) methyl iodide (10.0 μL, 0.15 mmol) and potassiumcarbonate (21.0 mg, 0.15 mmol) were combined in acetone (1.5 mL) andheated at reflux overnight. After cooling to room temperature, themixture was filtered and concentrated. Flash chromatography on silicagel (20% ethyl acetate/hexanes) afforded tert-Butyl4-((3-(1-methyl-1H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate(7.0 mg, 9%) and tert-Butyl4-((3-(2-methyl-2H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate(48 mg, 60%). Retention time: 4.75 min and 5.20 min. (Phenomenex C184.6×50 mm, 10% MeOH/90% H₂O/0.1% TFA→90% MeOH/10% H₂O/0.1% TFA, Gradienttime=6 min., Flow rate=4 mL/min.): Mass spec.: 532.31(MH)⁺ and532.31(MH)⁺ respectively.

Methyl 3-nitro-5-(trifluoromethyl)benzoate. 3-Nitro-5-(trifluoromethyl)benzoic acid (25.0 g, 106.3 mmol) was dissolved in methanol (60 mL)which was bubbled with hydrochloric acid gas for 1 h. The reaction wasallowed to stir at room temperature overnight and concentrated. Thecrude product was dissolved in ethyl acetate, washed with water (2×),brine (2×) dried over sodium sulfate and concentrated. Flashchromatography on silica gel afforded 23.4 g (88%) of the desiredcompound. ¹H-NMR (CDCl_(3,) 500 MHz) δ 9.02 (s, H), 8.66 (s, 1H), 8.61(s, 1H), 4.03 (s, 3H).

Methyl 3-amino-5-(trifluoromethyl)benzoate. Methyl3-nitro-5-(trifluoromethyl)benzoate (9.0 g, 36.1 mmol) in methanol (30mL) was flushed with nitrogen, and treated with palladium (10% oncharcoal, 0.90 g). The flask was flushed with hydrogen and allowed tostir under an atmosphere of hydrogen overnight. The reaction was flushedwith nitrogen, filtered through celite, and concentrated. Flashchromatography on silica gel (30% ethyl acetate/hexanes) afforded 6.8 g(86%). ¹H-NMR (CDCl_(3,) 500 MHz) δ 7.64 (s, H), 7.49 (s, 1H), 7.05 (s,1H), 3.91 (s, 3H). Mass spec.: 220.05 (MH)⁺.

Methyl 3-(5-methyl-1H-tetrazol-1-yl)-5-(trifluoromethyl)benzoate.Trimethylorthoacetate (0.41 mL, 3.4 mmol) in acetic acid (3 mL) wasadded dropwise to a solution of methyl3-amino-5-(trifluoromethyl)benzoate (0.5 g, 2.28 mmol) in acetic acid (5mL) at 75° C. After stirring for 45 min at 75° C., the reaction wastreated with sodium azide (0.21 g, 3.4 mmol) carefully in portions over15 min and stirring continued for 3 h. After cooling to roomtemperature, the reaction was concentrated and the residue dissolved inethyl acetate. This was washed with water (2×), 1 N hydrochloric acid(2×), brine (2×), dried over sodium sulfate, and concentrated. Flashchromatography on silica gel (20% ethyl acetate/hexanes) gave 0.38 g(58%). LC/MS (HPLC method 3): t_(R)=2.17 min, 287.12(MH)⁻.

3-(5-Methyl-1H-tetrazol-1-yl)-5-(trifluoromethyl)phenyl)methanol. Methyl3-(5-methyl-1H-tetrazol-1-yl)-5-(trifluoromethyl)benzoate (0.38 g, 1.33mmol) was dissolved in a diethyl ether (5 mL) and tetrahydrofuran (2.5mL) mixture and cooled to 0° C. The reaction was treated with water(24.0 μL, 1.33 mmol) and lithium borohydride (32.0 mg, 1.46 mmol),stirred at 0° C. for 30 min, and at room temperature for 1 h. Thereaction mixture was diluted with ethyl acetate, carefully quenched withmethanol (1.8 mL) and washed with water (2×), brine (2×), dried oversodium sulfate, and concentrated. Flash chromatography on silica gelgave 0.14 g (41%). ¹H-NMR (CDCl_(3,) 500 MHz) δ 7.83 (s, H), 7.75 (s,1H), 7.63 (s, 1H), 4.91 (s, 2H), 2.63 (s, 3H). Mass spec.: 259.10 (MH)⁺.

1-(3-(Bromomethyl)-5-(trifluoromethyl)phenyl)-5-methyl-1H-tetrazole.(3-(5-Methyl-1H-tetrazol-1-yl)-5-(trifluoromethyl)phenyl)methanol (110mg, 0.46 mmol) and triphenylphosphine (240 mg, 0.93 mmol) were combinedin methylene chloride (4 mL) and cooled to 0° C. N-Bromosuccinimide (171mg, 0.96 mmol) was introduced in portions and the reaction allowed towarm to room temperature. After 16 h, the reaction mixture was dilutedwith ethyl acetate, washed with concentrated sodium bicarbonate (2×),brine (2×), dried over sodium sulfate, and concentrated. Columnchromatography on silica gel (20% ethyl acetate/hexanes) gave 120 mg(82%). LC/MS (HPLC method 3): t_(R)=2.30 min, 323.01(MH)⁺.

tert-Butyl4-((3-(5-methyl-1H-tetrazol-1-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.1-(3-(Bromomethyl)-5-(trifluoromethyl)phenyl)-5-methyl-1H-tetrazole(30.0 mg, 0.09 mmol) and tert-butyl4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (29.0 mg, 0.1 mmol)were combined in dimethylformamide (2 mL) and cooled to 0° C. Thereaction was treated with sodium hydride (2.4 mg, 0.1 mmol), stirred at0° C. for 1 hr and at room temperature for 30 min. The reaction mixturewas diluted with water and extracted with ethyl acetate (2×). Theorganic layers were pooled together, washed with brine (2×), dried oversodium sulfate, and concentrated. Column chromatography on silica gel(40% ethyl acetate/hexanes) gave 40 mg (81%). LC/MS (HPLC method 3):t_(R)=3.14 min, 532.24(MH)⁺.

tert-Butyl4-((2-methoxy-5-nitrobenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.2-(Bromomethyl)-1-methoxy-4-nitrobenzene (100.0 mg, 0.34 mmol) andtert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (93.0 mg,0.38 mmol) were combined in dimethylformamide (4 mL) and cooled to 0° C.The reaction was treated with sodium hydride (9.0 mg, 0.38 mmol),stirred at 0° C. for 1 hr and at room temperature for 30 min. Thereaction mixture was diluted with water and extracted with ethyl acetate(2×). The organic layers were pooled together, washed with brine (2×),dried over sodium sulfate, and concentrated. Column chromatography onsilica gel (15% ethyl acetate/hexanes) gave 110 mg (71%). ¹H-NMR(CDCl_(3,) 500 MHz) δ 8.11 (dd, J=6.1, 3.1 Hz, 1H), 8.08 (d, J=2.8 Hz,1H), 7.34 (m, 4H), 7.21-7.24 (m, 1H), 6.80 (d, J=8.9 Hz, 1H), 4.37 (s,2H), 3.85 (s, 3H), 3.74-3.75 (m, 2H), 3.48 (s, 2H), 3.02-3.07 (m, 2H),2.21-2.24 (m, 2H), 1.87-1.93 (m, 2H), 1.43 (s, 9H). Mass spec.: 479.16(MNa)⁺.

tert-Butyl4-((5-amino-2-methoxybenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.tert-Butyl4-((2-methoxy-5-nitrobenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate(110 mg, 0.24 mmol) in methanol (3 mL) was flushed with nitrogen, andtreated with palladium (10% on charcoal, 11.0 mg). The flask was flushedwith hydrogen and allowed to stir under an atmosphere of hydrogenovernight. The reaction was flushed with nitrogen, filtered throughcelite, and concentrated to afford 96.0 mg (94%). ¹H-NMR (CDCl_(3,) 500MHz) δ 7.33-7.38 (m, 4H), 7.22-7.25 (m, 1H), 6.62 (d, J=8.5 Hz, 1H),6.51 (dd, J=5.8, 2.7 Hz, 1H), 6.29 (d, J=2.8 Hz, 1H), 4.37 (s, 2H),3.70-3.74 (m, 2H), 3.43 (s, 3H), 3.42 (s, 2H), 3.03-3.07 (m, 2H),2.15-2.18 (m, 2H), 1.88-1.93 (m, 2H), 1.43 (s, 9H). Mass spec.: 427.25(MH)⁺.

tert-Butyl4-((2-methoxy-5-(5-methyl-1H-tetrazol-1-yl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.Trimethylorthoacetate (40.0 μL, 0.32 mmol) in acetic acid (0.5 mL) wasadded dropwise to a solution of methyl3-amino-5-(trifluoromethyl)benzoate (0.5 g, 2.28 mmol) in acetic acid(1.5 mL) at 75° C. After stirring for 45 min at 75° C., the reaction wastreated with sodium azide (21.0 mg, 0.32 mmol) carefully and stirringcontinued for 3 h. After cooling to room temperature, the reaction wasconcentrated and the residue dissolved in ethyl acetate, washed withwater (2×), 1 N hydrochloric acid (2×), brine (2×), dried over sodiumsulfate, and concentrated. Flash chromatography on silica gel (30% ethylacetate/hexanes) gave 50.0 mg (56%). LC/MS (HPLC method 3): t_(R)=3.06min, 494.23(MH)⁺.

4-Bromo-2-(bromomethyl)-1-methoxybenzene. To a solution of(5-bromo-2-methoxyphenyl)methanol (1.0 g, 4.6 mmol) in dichloromethane(10 mL) at 0° C. was added tribromophosphine (1 M in dichloromethane,9.2 mL, 9.2 mmol). The ice bath was removed and the reaction stirred for15 min. The reaction was concentrated, poured onto cold saturated sodiumbicarbonate, extracted with pentane, dried over magnesium sulfate, andconcentrated to give 1.15 g (89%) as a white crystalline solid. ¹H NMR(500 MHz, CDCl₃) δ ppm 7.44 (d, J=2.5 Hz, 1H), 7.38 (dd, J=8.9, 6.1 Hz,1H), 4.47 (s, 2H), 3.87 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ ppm 156.7,133.6, 132.8, 128.4, 112.8, 112.7, 56.0, 27.5.

tert-Butyl4-((5-bromo-2-methoxybenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.To a solution of tert-butyl4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.40 g, 1.37 mmol)and 4-bromo-2-(bromomethyl)-1-methoxybenzene (0.46 g, 1.65 mmol) indimethylformamide (4 mL) at 0° C. was added sodium hydride (66 mg, 2.75mmol). After 20 min at 0° C., the ice bath was removed and the reactionstirred for 15 min. The reaction was poured into a separatory funnelcontaining ether and water. The ethereal was washed with water (2×),then brine, dried over magnesium sulfate, and concentrated. Columnchromatography (10% ethyl acetate/hexanes→25% ethyl acetate/hexanes)gave 640 mg (95%) as a colorless viscous oil. ¹H NMR (500 MHz, CDCl₃) δppm 7.20-7.45 (m, 7H), 6.65 (d, J=8.9 Hz, 1H), 4.36 (s, 2H), 3.76 (m,2H), 3.72 (s, 3H), 3.44 (s, 2H), 3.08 (m, 2H), 2.19 (m, 2H), 1.91 (m,2H), 1.44 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ ppm 155.8, 155.1, 143.0,130.8, 129.5, 128.6, 127.3, 126.5, 113.0, 111.8, 104.3, 79.8, 79.4,67.6, 55.6, 41.8, 40.3, 32.0, 28.6.

tert-Butyl4-((2-methoxy-5-(pyridin-4-yl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.A microwave tube was charged with tert-butyl4-((5-bromo-2-methoxybenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate(50 mg, 0.102 mmol), pyridin-4-ylboronic acid (50.1 mg, 0.408 mmol), andtetrakis(triphenylphosphine)-palladium(0) (12 mg, 10 μmol). The tube wasflushed with nitrogen, treated with tetrahydrofuran (2 mL) and potassiumhydroxide (1 M in water, 0.401 mL, 0.41 mmol). The tube was sealed andheated at 120° C. for 1 h via microwave. The reaction was cooled, pouredinto ether, washed with water (2×), then brine, dried over magnesiumsulfate, and concentrated. Column chromatography (ethyl acetate/hexanes)gave 26 mg (52%) as a colorless oil. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.61(d, J=5.8 Hz, 2H), 7.50 (dd, J=8.6, 2.5, 1H), 7.30-7.45 (m, 7H), 7.21(m, 1H), 6.89 (d, J=8.5, 1H), 4.47 (s, 2H), 3.82 (s, 3H), 3.73 (bs, 2H),3.50 (s, 2H), 3.07 (m, 2H), 2.20 (m, 2H), 1.91 (m, 2H), 1.42 (s, 9H);¹³C NMR (126 MHz, CDCl₃) δ ppm 157.7, 155.1, 150.1, 148.1, 143.3, 130.1,128.5, 128.1, 127.3, 126.7, 126.6, 126.4, 121.2, 110.6, 79.8, 79.3,67.9, 55.6, 41.8, 40.3, 32.2, 28.6. Mass spec.: 489.37 (MH)⁻.

tert-Butyl4-((5-(6-cyanopyridin-3-yl)-2-methoxybenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.A microwave tube was charged with tert-butyl4-((5-bromo-2-methoxybenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate(50 mg, 0.102 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (94 mg,0.408 mmol), and tetrakis(triphenylphosphine)-palladium(0) (11.78 mg,10.20 μmol). The tube was flushed with nitrogen, treated withtetrahydrofuran (2 mL) and potassium hydroxide (1 M in water, 0.41 mL,0.41 mmol). The tube was sealed and heated at 120° C. for 1 h viamicrowave. The reaction was cooled, poured into ether, washed with water(2×), then brine, dried over magnesium sulfate, and concentrated. Columnchromatography (ethyl acetate/hexanes) gave 46 mg (88%) as a colorlessoil. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.80 (d, J=2.1 Hz, 1H), 7.80 (dd,J=7.9, 2.1 Hz, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.44 (dd, J=8.5, 2.4 Hz,1H), 7.37 (m, 2H), 7.31 (m, 3H), 7.20 (m, 1H), 6.92 (d, J=8.5 Hz, 1H),4.47 (s, 2H), 3.83 (s, 3H), 3.73 (m, 2H), 3.50 (s, 2H), 3.06 (m, 2H),2.20 (m, 2H), 1.89 (m, 2H), 1.42 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ ppm157.8, 155.1, 149.3, 143.2, 139.6, 134.1, 131.5, 128.7, 128.5, 128.4,127.9, 127.3, 127.1, 126.6, 126.4, 117.6, 110.9, 102.9, 79.9, 79.4,67.7, 55.6, 41.8, 40.3, 32.2, 28.6. Mass spec.: 514.45 (MH)⁺.

tert-Butyl4-(((4′-cyano-4-methoxybiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate.A microwave tube was charged with tert-butyl4-((5-bromo-2-methoxybenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate(50 mg, 0.102 mmol), 4-cyanophenylboronic acid (60 mg, 0.41 mmol), andtetrakis(triphenylphosphine)-palladium(0) (12 mg, 10 μmol). The tube wasflushed with nitrogen, treated with tetrahydrofuran (2 mL) and potassiumhydroxide (1 M in water, 0.41 mL, 0.41 mmol). The tube was sealed andheated at 120° C. for 1 h via microwave. The reaction was cooled, pouredinto ether, washed with water (2×), then brine, dried over magnesiumsulfate, and concentrated. Column chromatography (12%→18% ethylacetate/hexanes) gave 47 mg (90%) as a white solid. ¹H NMR (500 MHz,CDCl₃) δ ppm 7.69 (d, J=8.5 Hz, 2H), 7.53 (d, J=8.5 Hz, 2H), 7.44 (dd,J=8.6, 2.4 Hz, 1H), 7.37 (m, 3H), 7.32 (m, 2H), 7.20 (m, 1H), 6.89 (m,1H), 4.48 (s, 2H), 3.82 (s, 3H), 3.74 (m, 2H), 3.50 (s, 2H), 3.07 (m,2H), 2.20 (m, 2H), 1.91 (m, 2H), 1.43 (s, 9H); ¹³C NMR (126 MHz, CDCl₃)δ ppm 157.4, 155.2, 145.4, 143.2, 134.2, 132.6, 131.3, 128.5, 128.1,127.3, 127.2, 126.9, 126.8, 126.3, 116.5, 110.6, 79.8, 79.5, 67.9, 55.6,41.8, 40.3, 32.2, 28.6. Mass spec.: 513.45 (MH)⁺.

tert-Butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate.1-(tert-Butoxycarbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylic acid(9.5 g, 29.3 mmol) was suspended in tetrahydrofuran (60 mL) and cooledto 0° C. To this solution was added borane tetrahydrofuran complex (1 Min tetrahydrofuran, 59 mL, 59 mmol) cautiously over 15 min. The reactionmixture was allowed to warm to room temperature overnight and thenheated at reflux for 24 h. The mixture was cooled to 0° C., treated withexcess methanol, diluted with ethyl acetate, washed with 1 N sodiumhydroxide (2×), then brine (2×), dried over sodium sulfate, andconcentrated. Column chromatography on silica gel (40% ethylacetate/hexanes) gave 6.6 g (72%) as a white powder. ¹H-NMR (CDCl_(3,)300 MHz) 7.24-7.29 (m, 2H), 7.00-7.05 (m, 2H), 3.66-3.71 (m, 2H), 3.49(s, 2H), 2.96-3.05 (m, 2H), 2.06-2.10 (m, 2H), 1.69-1.77 (m, 2H), 1.40(s, 9H). Mass spec.: 310.21 (MH)⁺.

tert-Butyl4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate.1-Bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (1.2 g, 3.78 mmol)and tert-butyl4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.96 g,3.2 mmol) were combined in dimethylformamide (10 mL) and cooled to 0° C.The reaction was treated with sodium hydride (151 mg, 6.3 mmol), stirredat 0° C. for 1 h, and at room temperature for 30 min. The reactionmixture was diluted with water and extracted with ethyl acetate (2×).The organic layers were pooled together, washed with brine (2×), driedover sodium sulfate, and concentrated. Column chromatography on silicagel (15% ethyl acetate/hexanes) gave 1.1 g (61%) as a clear oil. ¹H-NMR(CDCl₃, 500 MHz) δ 7.61 (s, 1H), 7.35 (s, 1H), 7.30-7.31 (m, 2H), 7.26(s, 1H), 7.03-7.07 (m, 2H), 4.36 (s, 2H), 3.72-3.75 (m, 2H), 3.38 (s,2H), 3.01-3.06 (m, 2H), 2.13-2.16 (m, 2H), 1.81-1.87 (m, 2H), 1.43 (s,9H). 13C-NMR (CDCl₃, 126 MHz) δ 161.6 (d, J=245.7 Hz), 152.0, 141.9,138.3, 133.3, 132.4 (q, J=32.6 Hz), 128.8, 127.5 123.2 (q, J=273.5 Hz),122.8, 122.4, 115.5, 115.3, 79.7, 79.5, 71.7, 68.0, 41.4, 32.2, 28.5,25.7. Mass spec.: 548.16 (MH)+.

tert-Butyl4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate.tert-Butyl4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate(130.0 mg, 0.24 mmol), 4-cyanophenylboronic acid (140.0 mg, 0.95 mmol),and tetrakis(triphenylphosphine) palladium(0) (37.1 mg, 0.024 mmol) werecombined in dry tetrahydrofuran (3 mL) in a microwave tube and sealed.The mixture was flushed with nitrogen. To this was added potassiumhydroxide (1 N in water, 0.75 mL, 0.75 mmol). The mixture was heated at120° C. for 1 h via microwave. After cooling to room temperature, thereaction mixture was concentrated and purified by flash chromatographyon silica gel (25% ethyl acetate/hexanes) to afford 61.0 mg (48%).¹H-NMR (CDCl_(3,) 500 MHz) δ 7.74-7.76 (m, 2H), 7.67 (s, 1H), 7.57-7.60(m, 2H), 7.41 (s, 1H), 7.40 (s, 1H), 7.29-7.32 (m, 2H),6.98-7.02 (m,2H), 4.47 (s, 2H), 3.71-3.74 (m, 2H), 3.43 (s, 2H), 3.01-3.06 (m, 2H),2.14-2.17 (m, 2H), 1.82-1.88 (m, 2H), 1.42 (s, 9H). Mass spec.: 569.25(MH)⁺.

1-(3-Bromo-5-(trifluoromethyl)phenyl)ethanone. A flask was charged withwater (42 ml), cooled to 0° C., and treated with concentratedhydrochloric acid (21.7 ml) and sulfuric acid (5.66 ml). To this wasadded 3-amino-5-bromobenzotrifluoride (8.77 ml, 62.5 mmol). The reactionwas treated with a solution of sodium nitrite (5.39 g, 78 mmol) in water(10 mL). The resulting reaction mixture was stirred for 30 min at 0° C.The reaction was transferred to a solution of acetaldoxime (5.71 ml, 94mmol) and copper(II) sulfate (0.499 g, 3.12 mmol) in water (30 mL) atroom temperature. After stirring for 1 h at room temperature, thereaction was heated to reflux and held there for 3 h. The reaction wascooled and diluted with pentane. It gave an intractable suspension. Thereaction mixture was filtered through a sintered glass funnel. Thelayers were separated. The organics were washed with water, then brine,dried over magnesium sulfate, and concentrated. The crude residue wasdistilled (high vacuum, 75° C.) to give 3 fractions of varying levels ofpurity. Total yield was 8.5 g (51%) with purity that ranged from 10:1 to1:1. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.25 (s, 1H), 8.11 (s, 1H), 7.95 (s,1H), 2.63 (s, 3H).

(±)-1-(3-Bromo-5-(trifluoromethyl)phenyl)ethanol. To a solution of1-(3-bromo-5-(trifluoromethyl)phenyl)ethanone (ca. 60% pure, 500 mg, 1.1mmol) in ethanol (10 mL) at 0° C. was added sodium borohydride (32 mg,0.85 mmol). The ice bath was removed and the reaction stirred at roomtemperature for 20 min. The reaction was cooled to 0° C., quenched bythe cautious addition of saturated ammonium chloride, and concentratedto remove most of the ethanol. The residue was dissolved in water andextracted with ether. The ethereal was washed with water, then brine,dried over magnesium sulfate, and concentrated. Column chromatography(8%→16% ethyl acetate/hexanes) gave 216 mg (72%) as a colorless oilwhich solidified upon standing. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.71 (s,1H), 7.66 (s, 1H), 7.56 (s, 1H), 4.93 (q, J=6.4 Hz, 1H), 2.03 (bs, 1H),1.50 (d, J=6.7 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ ppm 149.1, 132.6 (q,J=33.6 Hz), 132.1, 127.5 (q, J=3.8 Hz), 123.2 (q, J=273 Hz), 122.9,121.1 (q, J=3.8 Hz), 69.4, 25.5.

(±)-1-Bromo-3-(1-bromoethyl)-5-(trifluoromethyl)benzene. To a solutionof (±)-1-(3-bromo-5-(trifluoromethyl)phenyl)ethanol (390 mg, 1.45 mmol)and carbon tetrabromide (577 mg, 1.74 mmol) in tetrahydrofuran (2 mL) at0° C. was added triphenylphosphine (456 mg, 1.74 mmol). The resultingsolution was stirred at room temperature for 2 h. The reaction wastreated with an additional portion of carbon tetrabromide (289 mg, 0.87mmol)) and triphenylphosphine (228 mg, 0.87 mmol). The reaction wasstirred at room temperature for 1 h, diluted with several volumes ofpentane, and filtered to remove undissolved solids. The organics wereconcentrated and purified by column chromatography (1→3% ethylacetate/hexanes) to give 439 mg (91%) as a colorless oil. ¹H NMR (500MHz, CDCl₃) δ ppm 7.76 (s, 1H), 7.68 (s, 1H), 7.60 (s, 1H), 5.12 (q,J=7.0 Hz, 1H), 2.03 (d, J=7.0 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ ppm146.4, 133.5, 132.9 (q, J=32.6 Hz), 128.4 (q, J=3.8 Hz), 123.0, 123.0(q, J=273 Hz), 122.6 (q, J=3.8 Hz), 46.1, 26.6.

(±)-tert-Butyl4-((1-(3-bromo-5-(trifluoromethyl)phenyl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate.To a solution of tert-butyl4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (435 mg, 1.49 mmol)and (±)-1-bromo-3-(1-bromoethyl)-5-(trifluoromethyl)benzene (496 mg,1.49 mmol) in dimethylformamide (1.5 mL) at 0° C. was added sodiumhydride (72 mg, 3.0 mmol). The ice bath was removed and the resultingmixture stirred at room temperature for 1 h. The reaction was cooled to0° C., diluted with ether, and quenched by the cautious addition ofsaturated ammonium chloride. The mixture was poured into water andextracted into ether. The ethereal was washed with water, then brine,dried over magnesium sulfate, and concentrated. Column chromatography(8→12% ethyl acetate/hexanes) gave 188 mg (23%) as a colorless oil. ¹HNMR (500 MHz, CDCl₃) δ ppm 7.59 (s, 1H), 7.28-7.42 (m, 5H), 7.24 (m,2H), 4.17 (q, J=6.4 Hz, 1H), 3.76 (m, 2H), 3.27 (d, J=8.9 Hz, 1H), 3.21(d, J=8.9 Hz, 1H), 3.03 (m, 2H), 2.17 (m, 2H), 1.87 (m, 2H), 1.44 (s,9H), 1.28 (d, J=6.4 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ ppm 155.1,147.7, 142.6, 132.5 (q, J=32.6 Hz), 132.4, 128.5, 127.4 (q, J=3.8 Hz),127.2, 126.6, 123.2 (q, J=273 Hz), 122.8, 121.6 (q, J=3.8 Hz), 79.4,78.3, 41.7, 40.2, 32.1, 31.7, 28.6, 23.8. Mass spec.: 542.13 (MH)⁺.

(±)-tert-Butyl4-((1-(4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate.A microwave tube was charged with (±)-tert-butyl4-((1-(3-bromo-5-(trifluoromethyl)phenyl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate(40 mg, 0.074 mmol), 4-cyanophenylboronic acid (43 mg, 0.30 mmol), andtetrakis(triphenylphosphine) palladium(0) (8.5 mg, 7.4 μmol). The tubewas flushed with nitrogen, treated with tetrahydrofuran (2 mL) andpotassium hydroxide (1 M in water, 0.30 mL, 0.30 mmol). The tube wassealed and heated at 120° C. for 1 h via microwave. The reaction wascooled, poured into ether, washed with water (2×), then brine, driedover magnesium sulfate, and concentrated. Column chromatography (12%→25%ethyl acetate/hexanes) gave 36 mg (86%) as a colorless film. ¹H NMR (500MHz, CDCl₃) δ ppm 7.74 (m, 2H), 7.65 (s, 1H), 7.55 (m, 2H), 7.37 (s,2H), 7.26-7.34 (m, 4H), 7.17 (m, 1H), 4.30 (q, J=6.4 Hz, 1H), 3.74 (m,2H), 3.32 (m, 1H), 3.25 (m, 1H), 3.02 (m, 2H), 2.23 (m, 1H), 2.12 (m,1H), 1.75-1.97 (m, 2H), 1.43 (m, 9H), 1.35 (m, 3H). Mass spec.: 587.22(MNa)⁺.

(S)-1-(3-Bromo-5-(trifluoromethyl)phenyl)ethanol. A flask was chargedwith isopropanol (10 mL), dichloro(p-cymene)ruthenium (II) dimer (8.60mg, 0.014 mmol), and (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol (4.19 mg,0.028 mmol). After aging for 30 min,1-(3-bromo-5-(trifluoromethyl)phenyl)ethanone (375 mg, 1.4 mmol) wasadded and the reaction degassed by cooling it to −78° C., putting itunder high vacuum, venting to nitrogen, and repeating the process ca. 6times. The reaction was warmed to room temperature, treated with sodiumhydroxide (5 M in water, 0.013 mL, 0.063 mmol), and stirred at roomtemperature for 5 hours. The reaction was quenched by addition of 1 Mhydrochloric acid and extracted into pentane. The organics were washedwith water, then brine, dried over magnesium sulfate, and concentrated.Column chromatography (10→20% ethyl acetate/hexanes) gave 292 mg (77%)as a light brown oil. Chiral SFC (ChiralCel OD-H, 1:99 ethanol/carbondioxide) showed the optical purity to be 81% ee. ¹H NMR (500 MHz, CDCl₃)δ ppm 7.71 (s, 1H), 7.66 (s, 1H), 7.56 (s, 1H), 4.93 (q, J=6.4 Hz, 1H),2.03 (bs, 1H), 1.50 (d, J=6.7 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ ppm149.1, 132.6 (q, J=33.6 Hz), 132.1, 127.5 (q, J=3.8 Hz), 123.2 (q, J=273Hz), 122.9, 121.1 (q, J=3.8 Hz), 69.4, 25.5.

(S)-1-Bromo-3-(1-bromoethyl)-5-(trifluoromethyl)benzene. To a solutionof (S)-1-(3-bromo-5-(trifluoromethyl)phenyl)ethanol (150 mg, 0.56 mmol)in dichloromethane (3 mL) at 0° C. was added thionyl bromide (0.086 mL,1.12 mmol). The ice bath was removed and stirring continued for 1 h. Thereaction was warmed to reflux and held there for 1 h. The reaction wastreated with a second portion of thionyl bromide (0.086 mL, 1.12 mmol)and the reaction held at reflux for 2 h. The reaction was cooled to 0°C., quenched by addition of water, and diluted with pentane. Theorganics were washed with water (2×), then brine, dried over magnesiumsulfate, and concentrated. Column chromatography (100% hexanes) gave 78mg (42%). ¹H NMR (500 MHz, CDCl₃) δ ppm 7.76 (s, 1H), 7.68 (s, 1H), 7.60(s, 1H), 5.12 (q, J=7.0 Hz, 1H), 2.03 (d, J=7.0 Hz, 3H); ¹³C NMR (126MHz, CDCl₃) δ ppm 146.4, 133.5, 132.9 (q, J=32.6 Hz), 128.4 (q, J=3.8Hz), 123.0, 123.0 (q, J=273 Hz), 122.6 (q, J=3.8 Hz), 46.1, 26.6.

(R)-tert-butyl4-((1-(3-bromo-5-(trifluoromethyl)phenyl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate.To a solution of tert-butyl4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (65.8 mg, 0.23 mmol)and (S)-1-bromo-3-(1-bromoethyl)-5-(trifluoromethyl)benzene (75 mg, 0.23mmol) in dimethylformamide (0.4 mL) at 0° C. was added sodium hydride(10.8 mg, 0.45 mmol). The reaction was stirred at 0° C. for 1 h. Thereaction was quenched by addition of saturated ammonium chloride. Themixture was extracted with ether which was washed with water (2×), thenbrine, dried over magnesium sulfate, and concentrated to give 37 mg(30%) as a colorless oil. Chiral SFC (ChiralCel OJ-H, 1:99methanol/carbon dioxide) showed the optical purity to be 44% ee. ¹H NMR(500 MHz, CDCl₃) δ ppm 7.59 (s, 1H), 7.28-7.42 (m, 5H), 7.24 (m, 2H),4.17 (q, J=6.4 Hz, 1H), 3.76 (m, 2H), 3.27 (d, J=8.9 Hz, 1H), 3.21 (d,J=8.9 Hz, 1H), 3.03 (m, 2H), 2.17 (m, 2H), 1.87 (m, 2H), 1.44 (s, 9H),1.28 (d, J=6.4 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ ppm 155.1, 147.7,142.6, 132.5 (q, J=32.6 Hz), 132.4, 128.5, 127.4 (q, J=3.8 Hz), 127.2,126.6, 123.2 (q, J=273 Hz), 122.8, 121.6 (q, J=3.8 Hz), 79.4, 78.3,41.7, 40.2, 32.1, 31.7, 28.6, 23.8. Mass spec.: 542.13 (MH)⁺.

(R)-tert-Butyl4-((1-(4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate.A microwave tube was charged with (R)-tert-butyl4-((1-(3-bromo-5-(trifluoromethyl)phenyl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate(20 mg, 0.037 mmol), 4-cyanophenylboronic acid (21.7 mg, 0.15 mmol), andtetrakis(triphenylphosphine) palladium(0) (4.3 mg, 3.7 μmol). The tubewas flushed with nitrogen, treated with tetrahydrofuran (1 mL) andpotassium hydroxide (1 M in water, 0.15 mL, 0.15 mmol). The tube wassealed and heated at 120° C. for 1 h via microwave. The reaction wascooled, poured into ether, washed with water (2×), then brine, driedover magnesium sulfate, and concentrated. Column chromatography (12%→25%ethyl acetate/hexanes) gave 15.4 mg (74%) as a colorless film. ¹H NMR(500 MHz, CDCl₃) δ ppm 7.74 (m, 2H), 7.65 (s, 1H), 7.55 (m, 2H), 7.37(s, 2H), 7.26-7.34 (m, 4H), 7.17 (m, 1H), 4.30 (q, J=6.4 Hz, 1H), 3.74(m, 2H), 3.32 (m, 1H), 3.25 (m, 1H), 3.02 (m, 2H), 2.23 (m, 1H), 2.12(m, 1H), 1.75-1.97 (m, 2H), 1.43 (m, 9H), 1.35 (m, 3H). Mass spec.:587.22 (MNa)⁺.

(S)-1-(3-Bromo-5-(trifluoromethyl)phenyl)ethanol. A flask was flushedwith nitrogen, charged with isopropanol (15 mL), and degassed bybubbling nitrogen for 20 min. To this was addedbis-[rutheniumdichloride(p-cymene)] (0.017 g, 0.028 mmol), and(1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol (8.4 mg, 0.056 mmol). Themixture was stirred while bubbling nitrogen for 30 min. The resultingmixture was cooled to 0° C. and treated with1-(3-bromo-5-(trifluoromethyl)phenyl)ethanone (1.5 g, 5.62 mmol) andsodium hydroxide (5 M, 0.025 mL, 0.126 mmol). The reaction was stirredfor 7 h at 0° C. The reaction was quenched by addition of 1 Mhydrochloric acid and extracted into pentane (2×). The organics werewashed with brine, dried over magnesium sulfate, and concentrated.Column chromatography (10→20% ethyl acetate/hexanes) gave 1.45 g (96%)as a light yellow oil. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.71 (s, 1H), 7.66(s, 1H), 7.56 (s, 1H), 4.93 (q, J=6.4 Hz, 1H), 2.03 (bs, 1H), 1.50 (d,J=6.7 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ ppm 149.1, 132.6 (q, J=33.6Hz), 132.1, 127.5 (q, J=3.8 Hz), 123.2 (q, J=273 Hz), 122.9, 121.1 (q,J=3.8 Hz), 69.4, 25.5.

(S)-4-(1-(3-Bromo-5-(trifluoromethyl)phenyl)ethyl) 1-tert-butyl4-phenylpiperidine-1,4-dicarboxylate. To a suspension of1-(tert-butoxycarbonyl)-4-phenylpiperidine-4-carboxylic acid (1.98 g,6.47 mmol) in toluene (18 mL) and dichloromethane (3 mL) at 0° C. wasadded dicyclohexylcarbodiimide (1.56 g, 7.54 mmol) in small portions.The ice bath was removed and the resulting slurry stirred at roomtemperature for 30 min. The reaction was recooled to 0° C., treated with(S)-1-(3-bromo-5-(trifluoromethyl)phenyl)ethanol (1.45 g, 5.39 mmol) anddimethylaminopyridine (0.658 g, 5.39 mmol). The reaction was allowed towarm to room temperature overnight and stirred for 3 d. The reaction waspoured into pentane (˜100 mL). The resulting solid was filtered anddiscarded. The eluent was washed with 1 M hydrochloric acid, then 1 Msodium hydroxide, then brine, dried over magnesium sulfate, andconcentrated. Column chromatograpy (8%→12% ethyl acetate/hexanes) gave2.48 g (83%) as a colorless gum. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.58 (s,1H), 7.23-7.33 (m, 6H), 7.19 (s, 1H), 5.80 (q, J=3.82-3.97 (m, 2H),2.97-3.09 (m, 2H), 2.44-2.53 (m, 2H), 1.76-2.01 (m, 2H), 1.42 (s, 9H),1.40 (m, 3H). Mass spec.: 558.06 (MH)⁺.

(S)-tert-Butyl4-((1-(3-bromo-5-(trifluoromethyl)phenyl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate.To a solution of (S)-4-(1-(3-bromo-5-(trifluoromethyl)phenyl)ethyl)1-tert-butyl 4-phenylpiperidine-1,4-dicarboxylate (1.5 g, 2.70 mmol) indichloromethane (15 ml) at −78° C. was added diisobutylaluminum hydride(1 M in dichloromethane, 5.39 mL, 5.39 mmol) dropwise. The reaction wasstirred at −78° C. for 1 h, and treated with pyridine (0.654 ml, 8.09mmol), dimethylaminopyridine (0.659 g, 5.39 mmol), and acetic anhydride(1.53 ml, 16.2 mmol). The reaction was allowed to slowly warm to −10° C.in the dewar over 2 h. The reaction was diluted with diethyl ether,quenched by a few drops of methanol, and treated with saturated sodiumpotassium tartrate. The suspension was stirred vigorously at roomtemperature for a couple of hours. The mixture was poured into aseparatory funnel and the layers separated. The aqueous was extractedwith diethyl ether twice more. The pooled organics were washed with 1 Msodium bisulfate, then saturated sodium bicarbonate, then brine, driedover magnesium sulfate, and concentrated. Column chromatography (ethylacetate/hexanes on silica gel that was pre-treated with 2% Et3N in ethylacetate/hexanes) gave the intermediate acetate (0.80 g, 49%) as an oilwhich was used immediately without purification. To a solution of theintermediate acetate (0.80 g, 1.3 mmol) and triethylsilane (1.06 ml,6.66 mmol) in dichloromethane (15 mL) at −78° C. was added borontrifluoride-etherate (0.253 mL, 2.0 mmol). The reaction was allowed toslowly warm to 0° C. in the dewar. The reaction was stirred at 0° C. for7 h, quenched by addition of saturated sodium bicarbonate, poured intodiethyl ether, and the layers separated. The ethereal was washed withwater, then brine, dried over magnesium sulfate, and concentrated.Column chromatography (8→12% ethyl acetate/hexanes) gave 36 mg (5%) as acolorless oil. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.59 (s, 1H), 7.28-7.42 (m,5H), 7.24 (m, 2H), 4.17 (q, J=6.4 Hz, 1H), 3.76 (m, 2H), 3.27 (d, J=8.9Hz, 1H), 3.21 (d, J=8.9 Hz, 1H), 3.03 (m, 2H), 2.17 (m, 2H), 1.87 (m,2H), 1.44 (s, 9H), 1.28 (d, J=6.4 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δppm 155.1, 147.7, 142.6, 132.5 (q, J=32.6 Hz), 132.4, 128.5, 127.4 (q,J=3.8 Hz), 127.2, 126.6, 123.2 (q, J=273 Hz), 122.8, 121.6 (q, J=3.8Hz), 79.4, 78.3, 41.7, 40.2, 32.1, 31.7, 28.6, 23.8. Mass spec.: 542.13(MH)⁺.

(R)-1-(3-Bromo-5-(trifluoromethyl)phenyl)ethanol. A flask was chargedwith isopropanol (10 mL), dichloro(p-cymene)ruthenium (II) dimer (32 mg,0.05 mmol), and (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (16 mg, 0.1mmol). After aging for 30 min,1-(3-bromo-5-(trifluoromethyl)phenyl)ethanone (2.8 g, 10.5 mmol) wasadded and the reaction degassed by cooling it to −78° C., putting itunder high vacuum, venting to nitrogen, and repeating the process ca. 6times. The reaction was warmed to 0° C., treated with sodium hydroxide(5 M in water, 48 μL, 0.23 mmol), stirred at 0° C. for 5 hours and atroom temperature overnight. The reaction was quenched by addition of 1 Mhydrochloric acid and extracted into pentane. The organics were washedwith water (2×), then brine (2×), dried over sodium sulfate, andconcentrated. Column chromatography (15% ethyl acetate/hexanes) gave2.79 g (99%) as a yellowish oil. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.69 (s,1H), 7.63 (s, 1H), 7.53 (s, 1H), 4.91 (q, J=6.6 Hz, 1H), 1.49 (d, J=6.6Hz, 3H).

(R)-4-(1-(3-Bromo-5-(trifluoromethyl)phenyl)ethyl) 1-tert-butyl4-phenylpiperidine-1,4-dicarboxylate. A suspension of1-(tert-butoxycarbonyl)-4-phenylpiperidine-4-carboxylic acid (3.8 g,10.3 mmol) in a dichloromethane (5 mL) and toluene (30 mL) mixture wastreated with 1,3-dicyclohexylcarbodiimide (2.96 g, 14.4 mmol) andstirred for 30 min. The suspension was cooled to 0° C. and treated with(R)-1-(3-bromo-5-(trifluoromethyl)phenyl)ethanol (2.79 g, 10.3 mmol) anddimethylaminopyridine (1.26 g, 10.3 mmol). The ice bath was removed andthe suspension stirred at room temperature for 60 h. The reactionmixture was poured into pentane, filtered, and the solids washed severaltimes with pentane. The filtrate was washed with 1 N hydrochloric acid(1×), water (2×), then 1 N sodium hydroxide, then brine (2×), dried oversodium sulfate, and concentrated. Flash chromatography on silica gel(12% ethyl acetate/hexanes) gave 4.8 g (84%) as a light yellow oil. ¹HNMR (500 MHz, CDCl₃) δ ppm 7.58 (s, 1H), 7.23-7.33 (m, 6H), 7.19 (s,1H), 5.80 (q, J=6.6 Hz, 1H), 3.82-3.97 (m, 2H), 2.97-3.09 (m, 2H),2.44-2.53 (m, 2H), 1.76-2.01 (m, 2H), 1.42 (s, 9H), 1.40 (m, 3H). Massspec.: 558.06 (MH)⁺.

(R)-tert-Butyl4-((1-(3-bromo-5-(trifluoromethyl)phenyl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate.(R)-4-(1-(3-Bromo-5-(trifluoromethyl)phenyl)ethyl) 1-tert-butyl4-phenylpiperidine-1,4-dicarboxylate (3.8 g, 6.9 mmol) was dissolved inmethylene chloride (40 mL), cooled to −78° C. and treated withdiisobutylaluminum hydride (1 M in methylene chloride (13.8 mL, 13.8mmol). After stirring at −78° C. for 1 h, the reaction was treated withpyridine (1.64 mL, 20.6 mmol), dimethylaminopyridine (1.68 g, 13.8mmol), and acetic anhydride (2.9 mL, 41.2 mmol). The reaction was warmedto −10° C. over several hours in a dewar, quenched by addition of a fewdrops of methanol (until no bubbling was observed) followed by additionof excess saturated sodium potassium tartarate. The reaction was stirredat room temperature overnight. The layers were separated and the organiclayer washed with brine (2×), dried over sodium sulfate, andconcentrated to afford a precipitate which was immediately dissolved inmethylene chloride (50 mL) and treated with triethylsilane (6.7 mL, 45.3mmol). The solution was cooled to −78° C. and treated with borontrifluoride diethyl etherate (1.8 mL, 3.8 mmol). After 1 h, the reactionmixture was allowed to warm slowly to 0° C. and stirred for 7 h. Thereaction was quenched by addition concentrated sodium bicarbonate andthe layers were separated. The organic layer was washed with water (2×),then brine (2×), dried over sodium sulfate, and concentrated. Flashchromatography on silica gel (10% ethyl acetate/hexanes) gave 1.7 g in a1:1 ratio of the desired material and the ester starting material whichcould not be separated. The mixture in 1:1 tetrahydrofuran/methanol (12mL) at room temperature was treated with a solution of lithium hydroxidemonohydrate (271 mg, 1.62 mmol) in water (6 mL). The solution wasstirred at room temperature for 1 h, diluted with ethyl acetate, washedwith water (2×), then brine (2×), dried over sodium sulfate, andconcentrated to afford 900 mg (24%) as a clear oil. Chiral SFC(ChiralCel OJ-H, 1:99 methanol/carbon dioxide) showed the optical purityto be 92% ee. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.59 (s, 1H), 7.29-7.36 (m,5H), 7.22-7.25 (m, 2H), 4.16 (q, J=6.4 Hz, 1H), 3.74 (m, 2H), 3.25 (d,J=9.2 Hz, 1H), 3.21 (d, J=8.9 Hz, 1H), 2.99-3.06 (m, 2H), 2.11-2.21 (m,2H), 1.83-1.90 (m, 2H), 1.43 (s, 9H), 1.28 (m, 3H). Mass spec.: 544.01(MH)⁺.

(R)-tert-Butyl4-((1-(4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate.(R)-tert-Butyl4-((1-(3-bromo-5-(trifluoromethyl)phenyl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate(0.35 g, 0.65 mmol), 4-cyanophenylboronic acid (284 mg, 1.93 mmol), andtetrakis(triphenylphosphine) palladium(0) (75 mg, 0.07 mmol) werecombined in dry tetrahydrofuran (5 mL) in a microwave tube and sealed.After flushing with nitrogen, 2.3 mL of a 1 N potassium hydroxideaqueous solution was introduced. The mixture was heated at 120° C. for 1h via microwave. After cooling to room temperature, the reaction mixturewas concentrated and purified by flash chromatography on silica gel (15%ethyl acetate/hexanes) to afford 300 mg (82%) as an oil. LC/MS:t_(R)=3.51 min, 565.23 (MH)⁺. (Phenomenex C18 4.6×50 mm, 10% MeOH/90%H₂O/0.1% TFA→90% MeOH/10% H₂O/0.1% TFA, Gradient time=4 min., Flowrate=4 mL/min.).

tert-Butyl4-(((4′-fluoro-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate.¹H-NMR (CDCl₃, 500 MHz) δ 7.64 (s, 1H), 7.46 (m, 2H), 7.40 (s, 1H),7.28-7.35 (m, 3H), 7.15 (m, 2H), 7.01 (m, 2H), 4.46 (s, 2H), 3.73 (m,2H), 3.43 (s, 2H), 3.05 (m, 2H), 2.16 (m, 4H), 1.86 (m, 2H), 1.43 (s,9H); ¹³C NMR (126 MHz, CDCl₃) δ ppm 164.0, 162.5, 162.1, 160.5, 155.0,141.2, 140.3, 138.6 (m), 135.8 (m), 131.5 (q, J=32 Hz), 128.9, 129.83,128.80, 124.1 (q, J=273 Hz), 122.9 (q, J=3.8 Hz), 122.6 (q, J=3.8 Hz),116.1, 115.9, 115.4, 115.2, 79.5, 72.5, 41.3, 40.1, 32.3, 28.5.

(±)-tert-Butyl4-((1-(4′-cyano-5-fluorobiphenyl-3-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate.¹H-NMR (CDCl₃, 500 MHz) δ 7.71 (d, J=8.2 Hz, 2H), 7.54 (d, J=8.2 Hz,2H), 7.32 (m, 4H), 7.20 (m, 1H), 7.10 (m, 1H), 7.00 (s, 1H), 6.77 (d,J=9.2 Hz, 1H), 4.22 (q, J=6.4 Hz, 1H), 3.74 (m, 2H), 3.27 (q_(AB),J_(AB)=9.2 Hz, 2H), 3.02 (m, 2H), 2.21 (m, 1H), 2.13 (m, 1H), 1.88 (m,2H), 1.43 (s, 9H), 1.32 (d, J=6.4 Hz, 3H). Mass spec.: 515.32 (MH)⁺.

(S)-tert-Butyl4-((1-(4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate.A microwave tube was charged with (S)-tert-butyl4-((1-(3-bromo-5-(trifluoromethyl)phenyl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate(36 mg, 0.066 mmol), 4-cyanophenylboronic acid (39 mg, 0.27 mmol), andtetrakis(triphenylphosphine) palladium(0) (7.7 mg, 6.6 μmol). The tubewas flushed with nitrogen, treated with tetrahydrofuran (2 mL) andpotassium hydroxide (1 M in water, 0.265 mL, 0.265 mmol). The tube wassealed and heated at 110° C. for 1 h via microwave. The reaction wascooled, poured into diethyl ether, washed with water (2×), then brine,dried over magnesium sulfate, and concentrated. Column chromatography(12%→15% ethyl acetate/hexanes) gave 21 mg (56%) as a white foam solid.¹H NMR (500 MHz, CDCl₃) δ ppm 7.74 (m, 2H), 7.65 (s, 1H), 7.55 (m, 2H),7.37 (s, 2H), 7.26-7.34 (m, 4H), 7.17 (m, 1H), 4.30 (q, J=6.4 Hz, 1H),3.74 (m, 2H), 3.32 (m, 1H), 3.25 (m, 1H), 3.02 (m, 2H), 2.23 (m, 1H),2.12 (m, 1H), 1.75-1.97 (m, 2H), 1.43 (m, 9H), 1.35 (m, 3H). Mass spec.:587.22 (MNa)⁺.

(3-Bromo-5-fluorophenyl)methanol. 3-Bromo-5-fluorobenzoic acid (1.0 g,4.52 mmol) was suspended in tetrahydrofuran (8 mL) and cooled to 0° C.To this solution was added borane tetrahydrofuran complex (1 M intetrahydrofuran, 9 mL, 9.0 mmol) cautiously over 15 min. The reactionmixture was allowed to warm to room temperature overnight. The mixturewas cooled to 0° C., treated with excess methanol, diluted with ethylacetate, washed with 1 N sodium hydroxide (2×), then brine (2×), driedover sodium sulfate, and concentrated to afford 0.88 g (95%) as a whitepowder. ¹H-NMR (CDCl_(3,) 500 MHz) 7.29 (s, 1H), 7.16 (d, J=7.9 Hz, 1H),7.03 (d, J=9.2 Hz, 1H), 4.66 (s, 2H).

1-Bromo-3-(bromomethyl)-5-fluorobenzene.(3-Bromo-5-fluorophenyl)methanol (0.78 g, 3.8 mmol) andtriphenylphosphine (2.0 g, 7.6 mmol) were combined in tetrahydrofuran(20 mL) and cooled to 0° C. N-Bromosuccinimide (1.4 g, 7.98 mmol) wasintroduced in portions and the reaction allowed to warm to roomtemperature. After 16 h, the reaction mixture was diluted with ethylacetate, washed with concentrated sodium bicarbonate (2×), then brine(2×), dried over sodium sulfate, and concentrated. Column chromatographyon silica gel (5% ethyl acetate/hexanes) gave 0.8 g (79%) as a whitepowder. ¹H-NMR (CDCl_(3,) 300 MHz) 7.30 (s, 1H), 7.14-7.18 (m, 1H),7.01-7.05 (m, 1H), 4.36 (s, 2H).

tert-Butyl4-((3-bromo-5-fluorobenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.1-Bromo-3-(bromomethyl)-5-fluorobenzene (0.8 g, 3.0 mmol) and tert-butyl4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.72 g, 2.5 mmol)were combined in dimethylformamide (8 mL) and cooled to 0° C. Thereaction was treated with sodium hydride (120 mg, 4.98 mmol), stirred at0° C. for 1 h, and at room temperature for 30 min. The reaction mixturewas diluted with water and extracted with ethyl acetate (2×). Theorganic layers were pooled together, washed with brine (2×), dried oversodium sulfate, and concentrated. Column chromatography on silica gel(20% ethyl acetate/hexanes) gave 1.2 g (84%). ¹H-NMR (CDCl_(3,) 500 MHz)δ 7.34-7.38 (m, 4H), 7.24-7.25 (m, 1H), 7.08-7.10 (m, 1H), 7.01 (s, 1H),6.70-6.72 (m, 1H), 4.29 (s, 2H), 3.74-3.77 (m, 2H), 3.38 (s, 2H),3.00-3.06 (m, 2H), 2.17-2.20 (m, 2H), 1.84-1.90 (m, 2H), 1.44 (s, 9H).Mass spec.: 501.32 (MNa)⁺.

3-Bromo-5-fluorobenzaldehyde. To a solution of(3-bromo-5-fluorophenyl)methanol (2 g, 9.75 mmol) and triethylamine(2.72 mL, 19.5 mmol) in dimethylsulfoxide (25 mL) at 10° C. was addedsulfur trioxide-pyridine (3.11 g, 19.5 mmol) in several portions. Themixture was stirred at room temperature for 30 min. The reaction waspoured into ice water/pentane and the layers separated. The organicswere washed with 1 M potassium bisulfate, then water, then brine, driedover magnesium sulfate, and concentrated. Column chromatography (3%ethyl acetate/hexanes) gave 1.45 g (73%) as a white solid. ¹H-NMR(CDCl₃, 500 MHz) δ 9.92 (d, J=1.8 Hz, 1H), 7.80 (m, 1H), 7.50 (m, 2H);¹³C NMR (126 MHz, CDCl₃) δ ppm 189.2, 164.0, 162.0, 139.3, 129.0 (m),125.0, 124.8, 123.8, 123.7, 114.8, 114.6.

(±)-1-(3-Bromo-5-fluorophenyl)ethanol. To a solution of3-bromo-5-fluorobenzaldehyde (1.45 g, 7.14 mmol) in tetrahydrofuran (15mL) at −78° C. was added methylmagnesium bromide (3M in diethyl ether,2.98 mL, 8.93 mmol). The reaction was stirred at −78° C. for 30 min andthen at 0° C. for 30 min. The reaction was quenched by addition ofsaturated ammonium chloride and poured into pentane/water. The organicswere washed with water (2×), then brine, dried over magnesium sulfate,and concentrated. Column chromatography (12%→25% ethyl acetate/hexanes)gave 1.38 g (88%) as a colorless oil. ¹H-NMR (CDCl₃, 500 MHz) δ 7.29 (s,1H), 7.13 (m, 1H), 7.02 (m, 1H), 4.84 (q, J=6.4 Hz, 1H), 2.06 (bs, 1H),1.46 (d, J=6.4 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ ppm 163.9, 161.9,150.1 (m), 124.5 (m), 122.7, 122.6, 118.1, 117.9, 111.6, 111.4, 69.4,25.3.

(±)-1-Bromo-3-(1-bromoethyl)-5-fluorobenzene. To a solution of(±)-1-(3-bromo-5-fluorophenyl)ethanol (1.0 g, 4.6 mmol) and carbontetrabromide (1.82 g, 5.48 mmol) in tetrahydrofuran (5 mL) at 0° C. wasadded triphenylphosphine (1.44 g, 5.48 mmol). The resulting solution wasstirred at room temperature for 45 min. The reaction was diluted withseveral volumes of pentane, and filtered to remove the undissolvedsolids which were discarded. The organics were concentrated and purifiedby column chromatography (1% ethyl acetate/hexanes) to give 1.26 g (98%)as a colorless oil. ¹H-NMR (CDCl₃, 500 MHz) δ 7.35 (s, 1H), 7.17 (m,1H), 7.09 (m, 1H), 5.06 (q, J=7.0 Hz, 1H), 2.00 (d, J=7.0 Hz, 3H); ¹³CNMR (126 MHz, CDCl₃) δ ppm 163.6, 161.6, 147.2 (m), 126.0 (m), 122.8,122.7, 119.2, 119.0, 113.3, 113.1, 46.5, 26.7.

(±)-tert-Butyl4-((1-(3-bromo-5-fluorophenyl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate.To a solution of tert-butyl4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (827 mg, 2.84 mmol)and (±)-1-bromo-3-(1-bromoethyl)-5-fluorobenzene (800 mg, 2.84 mmol) indimethylformamide (3 mL) at 0° C. was added sodium hydride (75 mg, 3.1mmol). The ice bath was removed and the resulting mixture stirred atroom temperature for 1 h. The reaction was cooled to 0° C., diluted withdiethyl ether, and quenched by the cautious addition of saturatedammonium chloride. The mixture was poured into water and extracted intodiethyl ether. The ethereal was washed with water, then brine, driedover magnesium sulfate, and concentrated. Column chromatography (12→18%ethyl acetate/hexanes) gave 260 mg (19%) as a colorless oil. ¹H-NMR(CDCl₃, 500 MHz) δ 7.33 (m, 4H), 7.24 (m, 1H), 7.06 (m, 1H), 6.95 (s,1H), 6.63 (d, J=9.2 Hz, 1H), 4.09 (t, J=6.4 Hz, 1H), 3.75 (m, 2H), 3.22(q_(AB), J_(AB)=8.9 Hz, 2H), 3.02 (m, 2H), 2.16 (m, 2H), 1.87 (m, 2H),1.44 (s, 9H), 1.25 (d, J=6.4 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ ppm163.8, 161.8, 155.1, 148.63, 148.57, 142.7, 128.5, 127.3, 126.5, 125.0(m), 122.5, 122.4, 118.0, 117.8, 111.9, 111.8, 79.4, 78.1, 77.5, 41.7,40.3 (br), 32.0, 31.7, 28.6, 23.8. Mass spec.: 492.15 (MH)⁺.

(3-Amino-5-bromophenyl)methanol (3-Bromo-5-nitrophenyl)methanol (3.9 g,16.8 mmol) in methanol (35 mL) was flushed with nitrogen, and treatedwith platinum (IV) oxide (390 mg). The flask was flushed with hydrogenand allowed to stir under an atmosphere of hydrogen for 1 h. Thereaction was flushed with nitrogen, filtered through celite, andconcentrated to afford 3.1 g (94%). ¹H-NMR (CDCl_(3,) 300 MHz) δ 6.95(s, 1H), 6.80 (s, 1H), 6.79 (s, 1H), 4.61 (s, 2H). Mass spec.: 203.96(MH)⁺.

3′-Amino-5′-(hydroxymethyl)biphenyl-4-carbonitrile. A microwave tube wascharged with (3-amino-5-bromophenyl)methanol (1.0 g, 4.98 mmol),4-cyanophenylboronic acid (2.2 g, 15 mmol), andtetrakis(triphenylphosphine) palladium(0) (77.6 mg, 0.05 mmol). The tubewas flushed with nitrogen, treated with tetrahydrofuran (6 mL) andpotassium hydroxide (2 M in water, 3.0 mL, 6.0 mmol). The tube wassealed and heated at 120° C. for 1 h via microwave. The reaction wascooled, poured into ethyl acetate, washed with water (2×), brine, driedover sodium sulfate, and concentrated. Column chromatography (10% ethylacetate/hexanes) gave 0.51 g (46%) as a colorless oil. LC/MS: t_(R)=1.25min, 225.11 (MH)⁺. (Phenomenex C18 4.6×50 mm, 10% MeOH/90% H₂O/0.1%TFA→90% MeOH/10% H₂O/0.1% TFA, Gradient time=4 min., Flow rate=4mL/min.).

3′-Chloro-5′-(hydroxymethyl)biphenyl-4-carbonitrile. A solution of3′-amino-5′-(hydroxymethyl)biphenyl-4-carbonitrile (120 mg, 0.54 mmol)in dry acetonitrile (1 mL) was added dropwise to a solution of copper(II) chloride (86 mg, 0.64 mmol) and tert-butyl nitrite (91 μL, 0.78mmol) in acetonitrile (2 mL) at 65° C. After stirring for 30 min at 65°C., the reaction mixture was cooled to room temperature, poured into a 1N hydrochloric acid solution, and extracted with ethyl acetate (2×). Theorganic layers were pooled together, washed with brine (2×), dried oversodium sulfate, and concentrated. Column chromatography on silica gel(20% ethyl acetate/hexanes) afforded 46 mg (35%). LC/MS: t_(R)=2.54 min,244.03 (MH)⁺. (Phenomenex C18 4.6×50 mm, 10% MeOH/90% H₂O/0.1% TFA→90%MeOH/10% H₂O/0.1% TFA, Gradient time=4 min., Flow rate=4 mL/min.).

3′-(Bromomethyl)-5′-chlorobiphenyl-4-carbonitrile.(3-Bromo-5-(trifluoromethyl)phenyl)methanol (34 mg, 0.14 mmol) andtriphenylphosphine (73.4 mg, 0.28 mmol) were combined in tetrahydrofuran(2 mL) and cooled to 0° C. N-Bromosuccinimide (51.1 mg, 0.29 mmol) wasintroduced in portions and the reaction allowed to warm to roomtemperature. After 16 h, the reaction mixture was diluted with ethylacetate, washed with concentrated sodium bicarbonate (2×), then brine(2×), dried over sodium sulfate, and concentrated. Column chromatographyon silica gel (5% ethyl acetate/hexanes) gave 40 mg (93%). ¹H-NMR(CDCl_(3,) 300 MHz) δ 7.71-7.74 (m, 2H), 7.62-7.64 (m, 2H), 7.45-7.47(m, 2H), 7.40-7.42 (m, 1H), 4.46 (s, 2H).

tert-Butyl4-(((5-chloro-4′-cyanobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate.3′-(Bromomethyl)-5′-chlorobiphenyl-4-carbonitrile (38.3 mg, 0.12 mmol)and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (30.3mg, 0.1 mmol) were combined in dimethylformamide (2 mL) and cooled to 0°C. The reaction was treated with sodium hydride (5 mg, 0.2 mmol),stirred at 0° C. for 1 h, and at room temperature for 30 min. Thereaction mixture was diluted with water and extracted with ethyl acetate(2×). The organic layers were pooled together, washed with brine (2×),dried over sodium sulfate, and concentrated. Column chromatography onsilica gel (25% ethyl acetate/hexanes) gave 35 mg (56%). ¹H-NMR(CDCl_(3,) 300 MHz) δ 7.71 (s, 1H), 7.68 (s, 1H), 7.55 (s, 1H), 7.52 (s,1H), 7.39 (s, 1H), 7.28-7.35 (m, 4H), 7.19-7.21 (m, 1H), 7.10-7.13 (m,2H), 4.36 (s, 2H), 3.69-3.76 (m, 2H), 3.41 (s, 2H), 2.97-3.06 (m, 2H),2.15-2.19 (m, 2H), 1.80-1.90 (m, 2H), 1.40 (s, 9H). Mass spec.: 517.21(MH)⁺.

3′-Chloro-5′-formylbiphenyl-4-carbonitrile. To a solution of3′-chloro-5′-(hydroxymethyl)biphenyl-4-carbonitrile (330 mg, 1.35 mmol)and triethylamine (0.377 mL, 2.71 mmol) in dimethylsulfoxide (5 mL) at10° C. was added sulfur trioxide-pyridine (259 mg, 1.63 mmol) in oneportion. The bath was removed and stirring continued for 30 min. Thereaction was poured into ice water and extracted with ethyl acetate (3×)and the layers separated. The organics were washed with 1 M potassiumbisulfate, then water, then brine, dried over magnesium sulfate, andconcentrated. Column chromatography (12%→50% ethyl acetate/hexanes) gave280 mg (86%) as a white solid. ¹H-NMR (CDCl₃, 500 MHz) δ 10.04 (s, 1H),8.01 (s, 1H), 7.89 (s, 1H), 7.85 (s, 1H), 7.80 (m, 2H), 7.75 (m, 2H).

(±)-3′-Chloro-5′-(1-hydroxyethyl)biphenyl-4-carbonitrile. To a solutionof 3′-chloro-5′-formylbiphenyl-4-carbonitrile (280 mg, 1.16 mmol) intetrahydrofuran (5 mL) at −78° C. was added methylmagnesium bromide (3Min diethyl ether, 0.772 mL, 2.32 mmol). The reaction was stirred at −78°C. for 15 min and then allowed to gradually warm to −20° C. over 1 h.The reaction was recooled to −78° C. and quenched by the dropwiseaddition of saturated ammonium chloride. The mixture was poured intowater and extracted into diethyl ether. The ethereal was washed withbrine, dried over magnesium sulfate, and concentrated. Columnchromatography (25%→50% ethyl acetate/hexanes) gave 171 mg (57%) as acolorless oil. ¹H-NMR (CDCl₃, 500 MHz) δ 7.69 (d, J=8.2 Hz, 2H), 7.64(d, J=8.2 Hz, 2H), 7.46 (s, 1H), 7.43 (s, 1H), 7.40 (s, 1H), 4.93 (q,J=6.4 Hz, 1H), 2.37 (bs, 1H), 1.51 (d, J=6.7 Hz, 3H); ¹³C NMR (126 MHz,CDCl₃) δ ppm 149.0, 144.3, 141.1, 135.2, 132.8, 127.9, 126.3, 125.9,122.6, 118.7, 111.7, 69.7, 25.6.

(±)-3′-(1-Bromoethyl)-5′-chlorobiphenyl-4-carbonitrile. To a solution of(±)-3′-chloro-5′-(1-hydroxyethyl)biphenyl-4-carbonitrile (171 mg, 0.664mmol) and carbon tetrabromide (264 mg, 0.796 mmol) in tetrahydrofuran (2mL) at 0° C. was added triphenylphosphine (209 mg, 0.796 mmol). Theresulting solution was stirred at room temperature for 45 min. Thereaction was diluted with ca. 2 volumes of pentane and filtered toremove the undissolved solids which were discarded. The organics wereconcentrated and purified by column chromatography (3%→8% ethylacetate/hexanes) to give 201 mg (94%) as a colorless oil. ¹H-NMR (CDCl₃,500 MHz) δ 7.74 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.2 Hz, 2H), 7.50 (s, 1H),7.47 (s, 2H), 5.18 (q, J=6.7 Hz, 1H), 2.06 (d, J=7.0 Hz, 3H); ¹³C NMR(126 MHz, CDCl₃) δ ppm 146.1, 143.8, 141.5, 135.4, 132.8, 127.9, 127.3,127.1, 124.2, 118.6, 112.1, 47.4, 26.8.

(±)-tert-Butyl4-((1-(5-chloro-4′-cyanobiphenyl-3-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate.To a solution of tert-butyl4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (182 mg, 0.624 mmol)and (±)-3′-(1-bromoethyl)-5′-chlorobiphenyl-4-carbonitrile (200 mg,0.624 mmol) in dimethylformamide (1.5 mL) at 0° C. was added sodiumhydride (16.5 mg, 0.686 mmol). The reaction was stirred at roomtemperature for 1 h. The reaction was cooled to 0° C., diluted withdiethyl ether, and quenched by the cautious addition of saturatedammonium chloride. The mixture was poured into water and extracted intodiethyl ether. The ethereal was washed with water, then brine, driedover magnesium sulfate, and concentrated. Column chromatography (12→18%ethyl acetate/hexanes) gave 82 mg (25%) as a colorless foam. ¹H-NMR(CDCl₃, 500 MHz) δ 7.71 (d, J=8.5 Hz, 2H), 7.52 (d, J=8.5 Hz, 2H), 7.38(s, 1H), 7.31 (m, 4H), 7.18 (m, 1H), 7.07 (s, 1H), 7.05 (s, 1H), 4.20(q, J=6.4 Hz, 1H), 3.74 (m, 2H), 3.26 (q_(AB), J_(AB)=8.9 Hz, 2H), 3.01(m, 2H), 2.22 (m, 1H), 2.11 (m, 1H), 1.87 (m, 2H), 1.43 (s, 9H), 1.32(d, J=6.7 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ ppm 155.1, 147.3, 144.2,142.8, 141.0, 135.1, 132.7, 128.5, 127.9, 127.4, 126.4, 126.3, 126.2,122.9, 118.8, 111.7, 79.4, 78.1, 77.8, 41.6, 40.2 (br), 32.1, 31.7,28.6, 24.1. Mass spec.: 531.31 (MH)⁺.

Methyl 3-(hydroxymethyl)-5-nitrobenzoate.3-(Methoxycarbonyl)-5-nitrobenzoic acid (20.0 g, 88.9 mmol) was combinedwith tetrahydrofuran (150 mL) and cooled to 0° C. To this solution wasadded a 1 M borane tetrahydrofuran complex (178 mL, 178 mmol) cautiouslyover 15 min and the reaction mixture allowed to warm to room temperatureovernight. The mixture was cooled to 0° C., treated with excess methanoland concentrated in vacuo to afford to afford a precipitate which wasdissolved in ethyl acetate, washed with concentrated sodium bicarbonate(2×), then brine (2×), dried over sodium sulfate, and concentrated toafford 18.2 g (97%) which was used without further purification. ¹H-NMR(CDCl_(3,) 300 MHz) δ 8.70 (s, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 4.84 (s,2H), 3.95 (s, 3H). Mass spec.: 212.06 (MH)⁺.

Methyl 3-amino-5-(hydroxymethyl)benzoate. Methyl3-(hydroxymethyl)-5-nitrobenzoate (11.2 g, 53 mmol) in methanol (50 mL)was flushed with nitrogen, and treated with palladium (10% on charcoal,1.1 g). The flask was flushed with hydrogen and allowed to stir under anatmosphere of hydrogen overnight. The reaction was flushed withnitrogen, filtered through celite, and concentrated. Columnchromatography on silica gel (50% ethyl acetate/hexanes) afforded 2.8 g(29%). ¹H-NMR (CD₃OD, 300 MHz) δ 7.34 (s, 1H), 7.27 (s, 1H), 6.94 (s,1H), 4.55 (s, 2H), 3.88 (s, 3H). Mass spec.: 182.09 (MH)⁺.

Methyl 3-bromo-5-(hydroxymethyl)benzoate. Methyl3-amino-5-(hydroxymethyl)benzoate (2.4 g, 13.2 mmol) in dry acetonitrile(10 mL) was added dropwise to a solution of copper (II) bromide (3.54 g,15.8 mmol) and tert-butyl nitrite (2.24 mL, 18.9 mmol) in acetonitrile(20 mL) at 65° C. After stirring for 30 min at 65° C., the reactionmixture was cooled to room temperature, poured into a 1 N hydrochloricacid solution, and extracted with ethyl acetate (2×). The organic layerswere pooled together, washed with brine (2×), dried over sodium sulfate,and concentrated. Column chromatography on silica gel (30% ethylacetate/hexanes) afforded 2.0 g (62%). ¹H-NMR (CDCl_(3,) 300 MHz) δ 8.04(s, 1H), 7.90 (s, 1H), 7.69 (s, 1H), 4.70 (s, 2H), 3.89 (s, 3H). Massspec.: 246.98 (MH)⁺.

Methyl 3-bromo-5-(bromomethyl)benzoate. Methyl3-bromo-5-(hydroxymethyl)benzoate (2.0 g, 8.2 mmol) andtriphenylphosphine (4.28 g, 16.3 mmol) were combined in tetrahydrofuran(20 mL) and cooled to 0° C. N-Bromosuccinimide (3.05 g, 17.1 mmol) wasintroduced in portions and the reaction allowed to warm to roomtemperature. After 16 h, the reaction mixture was diluted with ethylacetate, washed with concentrated sodium bicarbonate (2×), then brine(2×), dried over sodium sulfate, and concentrated. Column chromatographyon silica gel (10% ethylacete/hexanes) gave 2.1 g (83%) as a light brownoil. ¹H-NMR (CDCl_(3,) 300 MHz) δ 8.07 (s, 1H), 7.96 (s, 1H), 7.70 (s,1H), 4.42 (s, 2H), 3.90 (s, 3H). Mass spec.: 308.93 (MH)⁺.

3-Bromo-5-(((1-(tert-butoxycarbonyl)-4-phenylpiperidin-4-yl)methoxy)methyl)benzoicacid. Methyl 3-bromo-5-(bromomethyl)benzoate (2.1 g, 6.81 mmol) andtert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (1.8 g,6.2 mmol) were combined in dimethylformamide (21 mL) and cooled to 0° C.The reaction was treated with sodium hydride (298 mg, 12.4 mmol),stirred at 0° C. for 1 h, and at room temperature for 30 min. Thereaction was cooled to 0° C. and treated lithium hydroxide monohydrate(0.54 g, 13.6 mmol). The solution was stirred at room temperature for 16h and the solvents evaporated. The resultant residue was diluted withwater (10 mL) and the pH adjusted to ca. 1 with 1 N hydrochloric acid.The resultant white suspension was stored at 4° C. overnight and theproduct was collected by filtration, washed with a small amount ofwater, and dried in vacuo for several hours to afford 2.4 g (70%) as awhite powder. LC/MS: t_(R)=3.33 min, 506.20 (MH)⁺. (Phenomenex C184.6×50 mm, 10% MeOH/90% H₂O/0.1% TFA→90% MeOH/10% H₂O/0.1% TFA, Gradienttime=4 min., Flow rate=4 mL/min.).

tert-Butyl4-((3-bromo-5-(dimethylcarbamoyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.A stirred solution of3-bromo-5-(((1-(tert-butoxycarbonyl)-4-phenylpiperidin-4-yl)methoxy)methyl)benzoicacid (160 mg, 0.32 mmol) in dimethylformamide (5 mL) was cooled to 0° C.and sequentially treated with methylene chloride (2 mL), dimethylamine(1 N in tetrahydrofuran, 0.32 mL, 0.32 mmol), N,N-diisopropylethylamine(90 μL, 0.64 mmol), and PyBop® (0.21 g, 0.38 mmol). The solution wasstirred for 1.5 h and concentrated. The product was purified by columnchromatography (30% ethyl acetate/hexanes) to give 120 mg (70%). ¹H-NMR(CDCl_(3,) 500 MHz) δ 7.38-7.40 (m, 1H), 7.33-7.35 (m, 4H), 7.22-7.24(m, 2H), 7.03 (s, 1H), 4.32 (s, 2H), 3.74-3.77 (m, 2H), 3.38 (s, 2H),3.08 (s, 3H), 2.99-3.05 (m, 2H), 2.90 (s, 3H), 2.16-2.19 (m, 2H),1.83-1.89 (m, 2H), 1.43 (s, 9H). Mass spec.: 533.24 (MH)⁺.

tert-Butyl4-((3-bromo-5-(piperidine-1-carbonyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.LC/MS: t_(R)=3.31 min, 573.38 (MH)⁺. (Phenomenex C18 4.6×50 mm, 10%MeOH/90% H₂O/0.1% TFA→90% MeOH/10% H₂O/0.1% TFA, Gradient time=4 min.,Flow rate=4 mL/min.).

tert-Butyl4-((3-bromo-5-(morpholine-4-carbonyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.LC/MS: t_(R)=3.15 min, 575.36 (MH)⁺. (Phenomenex C18 4.6×50 mm, 10%MeOH/90% H₂O/0.1% TFA→90% MeOH/10% H₂O/0.1% TFA, Gradient time=4 min.,Flow rate=4 mL/min.).

tert-Butyl4-(((5-carbamoyl-4′-fluorobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate.3-Bromo-5-(((1-(tert-butoxycarbonyl)-4-phenylpiperidin-4-yl)methoxy)methyl)benzoicacid (0.66 g, 1.31 mmol), 4-fluorophenylboronic acid (0.55 g, 3.93mmol), and tetrakis(triphenylphosphine) palladium(0) (82 mg, 0.05 mmol)were combined in dry tetrahydrofuran (10 mL) in a microwave tube andsealed. After flushing with nitrogen, 5.5 mL of a 1 N potassiumhydroxide aqueous solution was introduced. The mixture was heated at120° C. for 1 h via microwave. After cooling to room temperature, thereaction mixture was concentrated, dissolved in dimethylformamide (6 mL)and cooled to 0° C. The reaction mixture was sequentially treated withmethylene chloride (2 mL), 7 N ammonia in methanol (0.33 mL, 2.3 mmol),N,N-diisopropylethylamine (0.51 mL, 2.9 mmol), and PyBop® (0.72 g, 1.4mmol). The ice bath was removed and the solution stirred for 1.5 h andconcentrated. The product was purified by column chromatography (50%ethyl acetate/hexanes) to give 0.4 g (66%). ¹H-NMR (CDCl_(3,) 500 MHz) δ7.85 (s, 1H), 7.43-7.46 (m, 2H), 7.41 (s, 1H), 7.37 (s, 1H), 7.28-7.31(m, 4H), 7.15-7.18 9 (m, 1H), 7.07-7.10 (m, 2H), 4.40 (s, 2H), 3.67-3.69(m, 2H), 3.40 (s, 2H), 2.96-3.00 (m, 2H), 2.14-2.16 (m, 2H), 1.80-1.86(m, 2H), 1.37 (s, 9H). Mass spec.: 519.39 (MH)⁺.

tert-Butyl4-(((5-cyano-4′-fluorobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate.A stirred solution of tert-butyl4-(((5-carbamoyl-4′-fluorobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate(0.38 g, 0.72 mmol) in pyridine (6 mL) at 0° C. was treated withtrifluoroacetic anhydride (1.0 mL, 7.2 mmol). The ice bath was removedand the reaction stirred at room temperature for 4 h. The reaction wascooled to 0° C. and quenched by the addition of excess methanol. Thesolvents were evaporated and the crude mixture dissolved in ethylacetate and washed with 5% citric acid (2×), then water (2×), then brine(2×), dried over sodium sulfate, and concentrated. The residue waspurified by column chromatography (30% ethyl acetate/hexanes) to afford0.3 g (83%) as a white powder. ¹H-NMR (CDCl_(3,) 500 MHz) δ 7.65 (s,1H), 7.41-7.44 (m, 3H), 7.34-7.36 (m, 4H), 7.22-7.24 (m, 2H), 7.13-7.17(m, 2H), 4.41 (s, 2H), 3.75 (m, 2H), 3.44 (s, 2H), 2.01-3.06 (m, 2H),2.19-2.22 (m, 2H), 1.83-1.88 (m, 2H), 1.43 (s, 9H). Mass spec.: 501.37(MH)⁺.

(5-Amino-4′-fluorobiphenyl-3-yl)methanol. A dry round bottomed flask wascharged with (3-amino-5-bromophenyl)methanol (2.5 g, 12.4 mmol),4-fluorophenylboronic acid (5.2 g, 37.2 mmol), andtetrakis(triphenylphosphine) palladium(0) (0.39 g, 0.25 mmol). The flaskwas flushed with nitrogen and treated with tetrahydrofuran (30 mL) andpotassium hydroxide (2 M in water, 19 mL, 38 mmol). The mixture washeated at reflux for 4 h. The reaction was cooled, poured into ethylacetate, washed with water (2×), then brine, dried over magnesiumsulfate, and concentrated. Column chromatography (40% ethylacetate/hexanes) gave 1.52 g (56%) as a colorless oil. LC/MS: t_(R)=1.48min, 218.18 (MH)⁺. (Phenomenex C18 4.6×50 mm, 10% MeOH/90% H₂O/0.1%TFA→90% MeOH/10% H₂O/0.1% TFA, Gradient time=4 min., Flow rate=4mL/min.).

(5-Bromo-4′-fluorobiphenyl-3-yl)methanol. A solution of(5-bromo-4′-fluorobiphenyl-3-yl)methanol (1.52 g, 7.0 mmol) in dryacetonitrile (6 mL) was added dropwise to a solution of copper (II)bromide (1.88 g, 8.4 mmol) and tert-butyl nitrite (1.2 mL, 10.0 mmol) inacetonitrile (3 mL) at 65° C. After stirring for 30 min at 65° C., thereaction mixture was cooled to room temperature, poured into a 1 Nhydrochloric acid solution, and extracted with ethyl acetate (2×). Theorganic layers were pooled together, washed with brine (2×), dried oversodium sulfate, and concentrated. Column chromatography on silica gel(30% ethyl acetate/hexanes) afforded 420 mg (17%). ¹H-NMR (CDCl_(3,) 300MHz) δ 7.55-7.57 (m, 1H), 7.46-7.50 (m, 3H), 7.42 (m, 1H), 7.02-7.12 (m,2H), 4.70 (s, 2H).

3-Bromo-5-(bromomethyl)-4′-fluorobiphenyl.(5-Bromo-4′-fluorobiphenyl-3-yl)methanol (0.42 g, 1.5 mmol) andtriphenylphosphine (0.78 g, 2.98 mmol) were combined in tetrahydrofuran(8 mL) and cooled to 0° C. N-Bromosuccinimide (0.59 g, 3.1 mmol) wasintroduced in portions and the reaction allowed to warm to roomtemperature. After 16 h, the reaction mixture was diluted with ethylacetate, washed with concentrated sodium bicarbonate (2×), then brine(2×), dried over sodium sulfate, and concentrated. Column chromatographyon silica gel (5% ethyl acetate/hexanes) gave 0.4 g (78%) as a whitepowder. ¹H-NMR (CDCl_(3,) 500 MHz) 7.60 (m, 1H), 7.50-7.54 (m, 3H), 7.47(m, 1H), 7.12-7.15 (m, 2H), 4.47 (s, 2H).

tert-Butyl4-(((5-bromo-4′-fluorobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate.3-Bromo-5-(bromomethyl)-4′-fluorobiphenyl (398 mg, 1.16 mmol) andtert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (280 mg,0.96 mmol) were combined in dimethylformamide (5 mL) and cooled to 0° C.The reaction was treated with sodium hydride (46 mg, 1.92 mmol), stirredat 0° C. for 1 h, and at room temperature for 30 min. The reactionmixture was diluted with water and extracted with ethyl acetate (2×).The organic layers were pooled together, washed with brine (2×), driedover sodium sulfate, and concentrated. Column chromatography on silicagel (20% ethyl acetate/hexanes) gave 470 mg (73%). ¹H-NMR (CDCl_(3,) 500MHz) δ 7.51 (s, 1H), 7.28-7.42 (m, 6H), 7.19-7.23 (m, 2H), 7.06-7.14 (m,3H), 4.34 (s, 2H), 3.69-3.74 (m, 2H), 3.40 (s, 2H), 2.98-3.06 (m, 2H),2.14-2.19 (m, 2H), 1.81-1.90 (m, 2H), 1.41 (s, 9H). Mass spec.: 556.37(MH)⁺.

tert-Butyl4-(((4′-fluoro-5-hydroxybiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate.tert-Butyl4-(((5-bromo-4′-fluorobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate(0.47 g, 0.85 mmol) was dissolved in dry tetrahydrofuran (5 mL) andstirred at room temperature for 15 min. The stirred mixture was cooledto −78° C. and treated with a solution of n-butyllithium (1.6 M inhexanes, 0.61 mL, 0.98 mmol) over several minutes. After 30 min, themixture was treated with trimethylborate (0.28 mL, 2.55 mmol). Thereaction mixture was stirred at 78° C. for 1 h, then allowed to warm toroom temperature over several hours. The mixture was cooled to 0° C. andtreated with a 10 N sodium hydroxide solution (60 μL) and hydrogenperoxide (30% in water, 0.44 mL, 3.9 mmol). The reaction was warmed toroom temperature over several hours and then treated with saturatedammonium chloride. The reaction was diluted with ethyl acetate. Thelayers were separated and the organic layer washed with brine (2×),dried over sodium sulfate, filtered, and concentrated. Flashchromatography on silica gel (30% ethyl acetate/hexanes) afforded 280 mg(67%). ¹H-NMR (CDCl_(3,) 500 MHz) δ 7.38-7.43 (m, 2H), 7.19-7.35 (m,5H), 7.02-7.09 (m, 2H), 6.86-6.88 (m, 1H), 6.79 (s, 1H), 6.46 (s, 1H),4.33 (s, 2H), 3.70-3.74 (m, 2H), 3.38 (s, 2H), 2.98-3.07 (m, 2H),2.13-2.17 (m, 2H), 1.83-1.92 (m, 2H), 1.41 (s, 9H). Mass spec.: 492.41(MH)⁺.

5-Bromo-2-hydroxy-3-methylbenzoic acid. To a mixture of2-hydroxy-3-methylbenzoic acid (2.1 g, 13.5 mmol) in acetic acid (30 mL)was added bromine (0.7 mL, 13.7 mmol) slowly over 5 minutes. After 24 h,water was added slowly to the reaction mixture and the reaction stirredfor 30 min. The resulting precipitate was collected by filtration andwashed several times with water. The product was dried overnight underhigh vacuum to afford 2.8 g (90%). LC/MS: t_(R)=2.86 min, 229.14 (MH)⁺.(Phenomenex C18 4.6×50 mm, 10% MeOH/90% H₂O/0.1% TFA→90% MeOH/10%H₂O/0.1% TFA, Gradient time=4 min., Flow rate=4 mL/min.).

Methyl 5-bromo-2-methoxy-3-methylbenzoate.5-Bromo-2-hydroxy-3-methylbenzoic acid (2.8 g, 12.1 mmol), iodomethane(1.97 mL, 31.6 mmol) and potassium carbonate (16.9 g, 123 mmol) werecombined in dimethylformamide (30 mL). After stirring at roomtemperature for 16 h, the solvent was removed in vacuo and the crudeproduct dissolved in ethyl acetate, which was washed with water (2×),then brine (2×), dried over sodium sulfate, and concentrated. Flashchromatography on silica gel (10% ethyl acetate/hexanes) gave 2.26 g(72%). ¹H-NMR (CDCl_(3,) 500 MHz) δ 7.74-7.75 (m, 1H), 7.45-7.46 (m,1H), 3.90 (s, 3H), 3.80 (s, 3H), 2.28 (s, 3H). Mass spec.: 261.08 (MH)⁺.

(5-Bromo-2-methoxy-3-methylphenyl)methanol. Methyl5-bromo-2-methoxy-3-methylbenzoate (2.26 g, 8.7 mmol) was dissolved inmethylene chloride (30 mL), cooled to −78° C., and treated withdiisobutylaluminum hydride (1 M in methylene chloride, 26.1 mL, 26.1mmol). After stirring at −78° C. for 1 h the reaction was quenched by afew drops of methanol (until no bubbling was observed) followed byaddition of excess saturated sodium potassium tartarate (2 mL). Thereaction was stirred at room temperature overnight. The layers wereseparated and the organic layer washed with brine (2×), dried oversodium sulfate, and concentrated to afford 2.0 g (quant). ¹H-NMR(CDCl_(3,) 500 MHz) δ 7.30-7.31 (m, 1H), 7.21-7.22 (m, 1H), 4.62 (s,2H), 3.71 (s, 3H), 2.23 (s, 3H).

5-Bromo-1-(bromomethyl)-2-methoxy-3-methylbenzene.(5-Bromo-2-methoxy-3-methylphenyl)methanol (2.0 g, 8.7 mmol) andtriphenylphosphine (4.5 g, 17.4 mmol) were combined in tetrahydrofuran(30 mL) and cooled to 0° C. N-Bromosuccinimide (3.2 g, 17.4 mmol) wasintroduced in portions and the reaction allowed to warm to roomtemperature. After 16 h, the reaction mixture was diluted with ethylacetate, washed with concentrated sodium bicarbonate (2×), then brine(2×), dried over sodium sulfate, and concentrated. Column chromatographyon silica gel (hexanes) gave 1.87 g (73%) as a white powder. ¹H-NMR(CDCl_(3,) 300 MHz) δ 7.32-7.33 (m, 1H), 7.23-7.24 (m, 1H), 4.46 (s,2H), 3.82 (s, 3H), 2.25 (s, 3H).

tert-Butyl4-((5-bromo-2-methoxy-3-methylbenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.5-Bromo-1-(bromomethyl)-2-methoxy-3-methylbenzene (0.88 g, 3.0 mmol) andtert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.79 g,2.7 mmol) were combined in dimethylformamide (9 mL) and cooled to 0° C.The reaction was treated with sodium hydride (144 mg, 5.99 mmol),stirred at 0° C. for 1 h, and at room temperature for 30 min. Thereaction mixture was diluted with water and extracted with ethyl acetate(2×). The organic layers were pooled together, washed with brine (2×),dried over sodium sulfate, and concentrated. Column chromatography onsilica gel (10% ethyl acetate/hexanes) gave 1.24 g (82%). ¹H-NMR(CDCl_(3,) 500 MHz) δ 7.34-7.35 (m, 4H), 7.21-7.24 (m, 1H), 7.19-7.20(m, 1H), 7.10 (m, 1H), 4.34 (s, 2H), 3.72-3.76 (m, 2H), 3.53 (s, 3H),3.43 (s, 2H), 3.01-3.07 (m, 2H), 2.21 (s, 3H), 2.17-2.19 (m, 2H),1.85-1.91 (m, 2H), 1.43 (s, 9H). Mass spec.: 506.45 (MH)⁺.

tert-Butyl4-(((4,5-dicyanobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate.tert-Butyl4-(((5-bromo-4′-cyanobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate(52 mg, 0.09 mmol), tetrakis(triphenylphosphine) palladium(0) (14 mg,0.01 mmol), and zinc cyanide (12 mg, 0.1 mmol) were combined indimethylformamide (1.5 mL). The reaction mixture was degassed repeatedlyusing the freeze-pump-thaw method. After warming to room temperature,the reaction was heated at 90° C. for 1 h, cooled to room temperature,and concentrated. Flash chromatography on silica gel (30% ethylacetate/hexanes) gave 15 mg (33%). ¹H-NMR (CDCl_(3,) 300 MHz) δ7.78-7.75 (m, 3H), 7.52-7.55 (m, 2H), 7.31-7.33 (m, 4H), 7.20-7.23 (m,2H), 4.41 (s, 2H), 3.70-3.77 (m, 2H), 3.43 (s, 2H), 2.97-3.06 (m, 2H),2.17-2.21 (m, 2H), 1.78-1.88 (m, 2H), 1.40 (s, 9H). Mass spec.: 508.28(MH)⁺.

tert-Butyl4-(((4′-cyano-5-methylbiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate.A microwave tube was charged with tert-butyl4-(((5-bromo-4′-cyanobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate(48 mg, 0.09 mmol), trimethyl boroxine (13 μL, 0.09 mmol), andtetrakis(triphenylphosphine) palladium(0) (10 mg, 9 μmol). The tube wasflushed with nitrogen, treated with a mixture of 1,4-dioxane/water (9:1,2 mL) and potassium carbonate (35.1 mg, 0.25 mmol). The tube was sealedand heated at 120° C. for 1 h via microwave. After cooling to roomtemperature, the reaction was concentrated and purified by preparativeHPLC to give 11 mg (27%). LC/MS: t_(R)=3.50 min, 497.33 (MH)⁺.(Phenomenex C18 4.6×50 mm, 10% MeOH/90% H₂O/0.1% TFA→90% MeOH/10%H₂O/0.1% TFA, Gradient time=4 min., Flow rate=4 mL/min.).

(3-Bromo-5-nitrophenyl)methanol. 3-Bromo-5-nitrobenzoic acid (3.2 g,13.0 mmol) was suspended in tetrahydrofuran (25 mL) and cooled to 0° C.To this solution was added borane tetrahydrofuran complex (1 M intetrahydrofuran, 26 mL, 26 mmol) cautiously over 15 min. The reactionmixture was allowed to warm to room temperature overnight. The mixturewas cooled to 0° C., treated with excess methanol, diluted with ethylacetate, washed with 1 N sodium hydroxide (2×), then brine (2×), driedover sodium sulfate, and concentrated to afford 3.0 g (99%) as a whitepowder. ¹H-NMR (CDCl_(3,) 300 MHz) 8.24 (s, 1H), 8.13 (s, 1H), 7.82 (s,1H), 4.78 (s, 2H). Mass spec.: 233.88 (MH)⁺.

1-Bromo-3-(bromomethyl)-5-nitrobenzene. (3-Bromo-5-nitrophenyl)methanol(2.0 g, 8.65 mmol) and triphenylphosphine (4.5 g, 17.3 mmol) werecombined in tetrahydrofuran (40 mL) and cooled to 0° C.N-Bromosuccinimide (3.2 g, 18.2 mmol) was introduced in portions and thereaction allowed to warm to room temperature. After 16 h, the reactionmixture was diluted with ethyl acetate, washed with concentrated sodiumbicarbonate (2×), brine (2×), dried over sodium sulfate, andconcentrated. Column chromatography on silica gel (5% ethylacetate/hexanes) gave 2.2 g (84%) as a white powder. ¹H-NMR (CDCl_(3,)300 MHz) 8.27 (s, 1H), 8.16 (s, 1H), 7.84 (s, 1H), 4.45 (s, 2H).

tert-Butyl4-((3-bromo-5-nitrobenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.1-Bromo-3-(bromomethyl)-5-nitrobenzene (2.12 g, 7.21 mmol) andtert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (1.75 g,6.0 mmol) were combined in dimethylformamide (18 mL) and cooled to 0° C.The reaction was treated with sodium hydride (288 mg, 12.0 mmol),stirred at 0° C. for 1 h, and at room temperature for 30 min. Thereaction mixture was diluted with water and extracted with ethyl acetate(2×). The organic layers were pooled together, washed with brine (2×),dried over sodium sulfate, and concentrated. Column chromatography onsilica gel (20% ethyl acetate/hexanes) gave 1.4 g (38%). ¹H-NMR(CDCl_(3,) 500 MHz) δ 8.20 (s, 1H), 7.88 (s, 1H), 7.50 (s, 1H),7.33-7.38 (m, 4H), 4.37 (s, 2H), 3.75-3.78 (m, 2H), 3.43 (s, 2H),3.00-3.04 (m, 2H), 2.20-2.22 (m, 2H), 1.82-1.87 (m, 2H), 1.42 (s, 9H).Mass spec.: 507.10 (MH)⁺.

tert-Butyl4-((3-amino-5-bromobenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.tert-Butyl4-((3-bromo-5-nitrobenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate(1.36 g, 2.69 mmol) and tin (II) chloride dihydrate (6.48 g, 28.7 mmol)were combined in ethyl acetate (20 mL) and heated at reflux for 4 h.After cooling to room temperature, the reaction mixture was diluted withethyl acetate and washed with saturated sodium bicarbonate (2×), brine(2×), dried over sodium sulfate and concentrated. The crude product wasdissolved in tetrahydrofuran (10 mL), cooled to 0° C. and treated withdi-tert-butyl carbonate (0.59 g, 2.69 mmol) and 10 N sodium hydroxide(0.65 mL). The reaction was allowed to warm to room temperatureovernight. The reaction mixture was diluted with ethyl acetate, washedwith water (2×), brine (2×), dried over sodium sulfate and concentrated.Column chromatography on silica gel (30% ethyl acetate/hexanes) gave0.25 g (19%). LC/MS (HPLC method 3): t_(R)=2.99 min, 477.05(MH)⁺.

tert-Butyl4-(((5-amino-4′-cyanobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate.tert-Butyl4-((3-amino-5-bromobenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate(220.0 mg, 0.46 mmol), 4-cyanophenylboronic acid (273.0 mg, 1.86 mmol),and tetrakis(triphenylphosphine) palladium(0) (71.7 mg, 0.046 mmol) werecombined in dry tetrahydrofuran (5 mL) in a microwave tube and sealed.The mixture was flushed with nitrogen. To this was added potassiumhydroxide (1 N in water, 1.4 mL, 1.4 mmol). The mixture was heated at120° C. for 1 h via microwave. After cooling to room temperature, thereaction mixture was concentrated and purified by flash chromatographyon silica gel (25% ethyl acetate/hexanes) to afford 140.0 mg (61%).LC/MS (HPLC method 3): t_(R)=2.85 min, 498.24(MH)⁺.

tert-Butyl4-(((5-bromo-4′-cyanobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate.A solution of tert-Butyl4-(((5-amino-4′-cyanobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate(136.0 mg, 0.27 mmol) in dry acetonitrile (2.0 mL) was added dropwise toa solution of copper (II) bromide (71.6 g, 0.32 mmol) and tert-butylnitrite (46.0 μL, 0.39 mmol) in acetonitrile (1.0 mL) at 65° C. Afterstirring for 30 min at 65° C., the reaction mixture was cooled to roomtemperature, poured into a 1 N hydrochloric acid solution, and extractedwith ethyl acetate (2×). The organic layers were pooled together, washedwith brine (2×), dried over sodium sulfate, and concentrated. Columnchromatography on silica gel (20% ethyl acetate/hexanes) afforded 30.0 g(20%). ¹H-NMR (CDCl_(3,) 300 MHz) δ 7.68-7.71 (m, 2H), 7.51-7.55 (m,3H), 7.25-7.38 (m, 5H), 7.17-7.20 (m, 2H), 4.36 (s, 2H), 3.68-3.76 (m,2H), 3.41 (s, 2H), 2.97-3.06 (m, 2H), 2.14-2.19 (m, 2H), 1.80-1.89 (m,2H), 1.40 (s, 9H). Mass spec.: 563.12 (MH)⁺.

tert-Butyl 4-cyano-4-(pyridin-3-yl)piperidine-1-carboxylate. A flask wascharged with sodium hydride (5.08 g, 127 mmol) and dimethylformamide(100 ml) at 0° C. under nitrogen. 2-(Pyridin-3-yl)acetonitrile (5 g,42.3 mmol) was added in 25 mL of dimethylformamide via addition funnelover 20 min. After 20 min, tert-butyl bis(2-chloroethyl)carbamate (12.81g, 52.9 mmol) was added in 20 mL of dimethylformamide via additionfunnel over 20 min. The reaction was allowed to stir at 0° C. for 2 hand then at 60° C. for 12 h. The reaction was quenched with 10% sodiumbicarbonate (100 mL) and extracted with ethyl acetate (5×100 mL). Theorganics were collected, washed with brine, dried over sodium sulfate,and concentrated in vacuo. The residue was purified via columnchromatography (10% 2M ammonia in methanol, 90% dichloromethane) toyield 7.5 g (49%) of desired product. Mass Spec.: 288.20 (MH)⁺. LCt_(r)=1.380 min (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H₂O/0.1%TFA→90% MeOH/10% H₂O/0.1% TFA Gradient Time=2 min, Flow rate=4 mL/min)

1-(tert-Butoxycarbonyl)-4-(pyridin-3-yl)piperidine-4-carboxylic acid. Aflask was charged with tert-butyl4-cyano-4-(pyridin-3-yl)piperidine-1-carboxylate (7.5 g, 26.1 mmol) andNaOH (50% in water, 100 mL) in ethanol (100 ml) and heated at reflux for6 h. The ethanol was removed, and the resulting solution was acidifiedto pH=5 using concentrated hydrochloric acid. The desired product wascollected by filtration, and dried overnight to yield 4.1 g (51%). MassSpec. : 307.18 (MH)+. LC t_(r)=1.31 min (Phenomenex-Luna 4.6×50 mm S10,10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA Gradient Time=2 min,Flow rate=4 mL/min)

tert-Butyl 4-(hydroxymethyl)-4-(pyridin-3-yl)piperidine-1-carboxylate. Aflask was charged with1-(tert-butoxycarbonyl)-4-(pyridin-3-yl)piperidine-4-carboxylic acid(4.0 g, 13.1 mmol) and tetrahydrofuran (25 mL). The reaction was placedunder nitrogen. To the flask was added borane-tetrahydrofuran complex (1M in tetrahydrofuran, 26.1 mL, 26.1 mmol) and heated at reflux for 2 h.The reaction was cooled to 0° C. and quenched with methanol (100 mL).The solution was then concentrated in vacuo. The residue was purifiedvia column chromatography (5% methanol/95% dichloromethane) to yield 3.2g (84%). Mass Spec.: 293.26 (MH)⁺. LC: t_(r)=1.65 min (Phenomenex-Luna4.6×50 mm S10, 10% MeOH/90% H₂O/0.1% TFA→90% MeOH/10% H₂O/0.1% TFAGradient Time=2 min, Flow rate=4 mL/min).

tert-Butyl4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-(pyridin-3-yl)piperidine-1-carboxylate.A flask was charged with1-bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (2.53 g, 7.96 mmol)and tert-butyl4-(hydroxymethyl)-4-(pyridin-3-yl)piperidine-1-carboxylate (1.1 g, 3.8mmol) in tetrahydrofuran (10 mL) at 0° C. The reaction was treated withsodium tert-butoxide (364 mg, 3.79 mmol), stirred at 0° C. for 20 min,and treated with another aliquot of sodium tert-butoxide (364 mg, 3.79mmol). The reaction was allowed to warm to room temperature for 30 minthen diluted with 10% sodium bicarbonate and extracted with ethylacetate (2×). The organic layers were pooled together, washed with brine(1×), dried over sodium sulfate, and concentrated. Column chromatographyon silica gel (0%-60% ethyl acetate/hexanes) gave 1.23 g (62%). Massspec.: 529.12 (MH)⁺ LC t_(r)=2.248 min. (Phenomenex-Luna 4.6×50 mm S10,10% MeOH/90% H₂O/0.1% TFA→90% MeOH/10% H₂O/0.1% TFA Gradient Time=2 min,Flow rate=4 mL/min).

3-(4-((3-Bromo-5-(trifluoromethyl)benzyloxy)methyl)-1-methylpiperidin-4-yl)pyridine.A flask was charged with tert-butyl4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-(pyridin-3-yl)piperidine-1-carboxylate(900 mg, 1.70 mmol) in methanol (5 mL). Hydrochloric acid (gas) wasbubbled through for 20 seconds and the mixture was allowed to stir for20 min. The solvent was concentrated in vacuo. The solid whiteintermediate was redissolved in dichloromethane (5 mL) and treated withformaldehyde (37 wt. % solution in water, 1.5 mL) at 0° C. After 20 minthe reaction was treated with sodium triacetoxyborohydride (1.4 g, 6.8mmol). The reaction was stirred at 0° C. for 30 min and at roomtemperature for 1 h. The solvent was removed in vacuo and the resultingresidue purified via preparative HPLC to yield 330 mg (44%) of desiredproduct. Mass spec.: 443.03 (MH)⁺ LC t_(r)=1.398 min (Phenomenex-Luna4.6×50 mm S10, 10% MeOH/90% H₂O/0.1% TFA→90% MeOH/10% H₂O/0.1% TFAGradient Time=2 min, Flow rate=4 mL/min).

1-tert-Butyl 4-ethyl 4-(pyridin-4-yl)piperidine-1,4-dicarboxylate.Prepared in the same fashion as tert-butyl4-cyano-4-(pyridin-3-yl)piperidine-1-carboxylate. Mass Spec.: 335.01(MH)⁺. LC: t_(r)=1.460 min (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90%H₂O/0.1% TFA→90% MeOH/10% H₂O/0.1% TFA Gradient Time=2 min, Flow rate=4mL/min)

tert-Butyl 4-(hydroxymethyl)-4-(pyridin-4-yl)piperidine-1-carboxylate. Aflask was charged with 1-tert-butyl 4-ethyl4-(pyridin-4-yl)piperidine-1,4-dicarboxylate (250 mg, 0.748 mmol) intetrahydrofuran (3 mL) and cooled to −50° C. (acetonitrile/dry ice).Lithium aluminum hydride (0.785 ml, 1.570 mmol) was added dropwise, andthe reaction was allowed to stir for 30 min. The flask was then warmedto room temperature and slowly diluted with ethyl acetate (5 mL). Water(61 μL) was added and the reaction allowed to stir for 5 min. SodiumHydroxide (1 N in water, 120 μL) was then added and the reaction allowedto stir for 5 min. An additional portion of water (61 μL) and a smallamount of sodium sulfate was added and the resulting mixture allowed tostir for 5 min. The suspension was filtered through celite, and theresulting pad washed with hot ethyl acetate. The filtrate wasconcentrated in vacuo to yield 90 mg (41%) of desired product. MassSpec.: 294.05 (MH)⁺. LC t_(r)=1.79 min (HPLC Method 1).

tert-Butyl4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(pyridin-4-yl)piperidine-1-carboxylate.A flask was charged with3′-(bromomethyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile (157 mg,0.462 mmol) and tert-butyl4-(hydroxymethyl)-4-(pyridin-4-yl)piperidine-1-carboxylate (90 mg, 0.308mmol) in tetrahydrofuran (10 mL) at 0° C. The reaction was treated withpotassium tert-butoxide (34.6 mg, 0.308 mmol), stirred at 0° C. for 20min, and treated with another aliquot of potassium tert-butoxide (34.6mg, 0.308 mmol). The reaction was allowed to warm to room temperaturefor 30 min, then diluted with 10% sodium bicarbonate, and extracted withethyl acetate (2×). The organic layers were pooled together, washed withbrine (1×), dried over sodium sulfate, and concentrated. Columnchromatography on silica gel (0%→65% ethyl acetate/hexanes) gave 50 mg(29%). Mass spec.: 552.18 (MH)⁺ LC t_(r)=2.54 min (HPLC Method 1).

1-tert-butyl 4-methyl 4-(2-fluorophenyl)piperidine-1,4-dicarboxylate. Aflask was charged with sodium hydride (2.14 g, 89.2 mmol) anddimethylformamide (70 ml) at 0° C. under nitrogen. Methyl2-(2-fluorophenyl)acetate (5 g, 29.7 mmol) was added to the flask, andafter stirring for 25 min, tert-butyl bis(2-chloroethyl)carbamate (8.6g, 35.6 mmol) was added. The reaction was allowed to warm to rt andstirred overnight. The reaction was quenched with a saturated solutionof ammonium chloride and extracted with ethyl acetate (5×100 mL). Theorganics were collected, washed with brine, dried over sodium sulfate,and concentrated in vacuo. The residue was purified via silica gelchromatography (10/90→50/50 ethyl acetate/hexanes) to yield 1.7 g (17%)of the desired product. ¹H-NMR (CDCl₃, 400 MHz) δ ppm 7.29 (m, 1H), 7.24(m, 1H), 7.12 (m, 1H), 7.00 (m, 1H), 3.86 (m, 2H), 3.67 (m, 3H), 3.22(m, 2H), 2.37 (m, 2H), 1.96 (m, 2H), 1.44 (s, 9H). Mass spec.: 360.22(MNa)⁺. LC t_(r)=3.503 min (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90%H₂O/0.1% TFA→90% MeOH/10% H₂O/0.1% TFA Gradient Time=4 min, Flow rate=4mL/min)

1-(tert-butoxycarbonyl)-4-(2-fluorophenyl)piperidine-4-carboxylic acid.A flask was charged with 1-tert-butyl 4-methyl4-(2-fluorophenyl)piperidine-1,4-dicarboxylate (1.7 g, 5.04 mmol) andLiOH (2.11 g, 50.4 mmol) in 25 mL of a 4:1 THF:H2O solution. The flaskwas equipped with a reflux condenser and heated to reflux for 48 hr. Thereaction was cooled to rt, and the solution was acidified to pH=1 with6N hydrochloric acid. The aqueous solution was extracted with ethylacetate, and the organic layer was separated, washed with brine, anddried over Na₂SO₄. The organic solvent was evaporated in vacuo affording1.51 g (92%) of the desired acid. Mass Spec.: 347.23 (MNa)⁺. LCt_(r)=3.253 min (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H2O/0.1%TFA→90% MeOH/10% H2O/0.1% TFA Gradient Time=4 min, Flow rate=4 mL/min).

tert-butyl 4-(2-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate.A flask was charged with1-(tert-butoxycarbonyl)-4-(2-fluorophenyl)piperidine-4-carboxylic acid(1.51 g, 4.6 mmol) and tetrahydrofuran (10 mL). The reaction was placedunder nitrogen. To the flask was added borane-tetrahydrofuran complex (1M in tetrahydrofuran, 9.2 mL, 9.2 mmol). The reaction was allowed tostir at rt for 48 hr. The reaction was cooled to 0° C. and quenched withmethanol (50 mL). The solution was then concentrated in vacuo. Theresidue was purified via column chromatography (25% ethyl acetate/75%hexanes→60% ethyl acetate/hexanes) to yield 1.0 g (70%) of the desiredalcohol. ¹H-NMR (CDCl₃, 400 MHz) δ ppm 7.26 (m, 2H), 7.11 (m, 1H), 7.01(m, 1H), 3.72 (m, 4H), 3.09 (m, 2H), 2.27 (m, 2H), 1.79 (m, 2H), 1.42(s, 9H). Mass Spec.: 332.18 (MNa)⁻. LC: t_(r)=3.301 min (Phenomenex-Luna4.6×50 mm S10, 10% MeOH/90% H₂O/0.1% TFA→90% MeOH/10% H₂O/0.1% TFAGradient Time=4 min, Flow rate=4 mL/min).

tert-butyl4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-(2-fluorophenyl)piperidine-1-carboxylate.A flask was charged with1-bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (0.149 g, 0.47 mmol)and tert-butyl4-(2-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.1 12 g,0.36 mmol) in tetrahydrofuran (2 mL) at 0° C. The reaction was treatedwith potassium tert-butoxide (0.41 mg, 0.36 mmol), stirred at 0° C. for20 min, and treated with another aliquot of potassium tert-butoxide(0.41 mg, 0.36 mmol). The reaction was allowed to warm to roomtemperature and was stirred for 16 h. The reaction mixture wasevaporated in vacuo and the crude oil was purified by silica gelchromatography (5% ethyl acetate/95% hexanes→30% ethyl acetate/70%hexanes) to afford 0.138 g (70%) of the desired ether. Mass spec.:546.03 (MH)⁺ LC t_(r)=4.501 min. (Phenomenex-Luna 4.6×50 mm S10, 10%MeOH/90% H₂O/0.1% TFA→90% MeOH/10% H₂O/0.1% TFA Gradient Time=4 min,Flow rate=4 mL/min).

tert-butyl4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(2-fluorophenyl)piperidine-1-carboxylate.A sealable vial was charged with tert-butyl4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-(2-fluorophenyl)piperidine-1-carboxylate(0.138 g, 0.25 mmol) and 4-cyanophenylboronic acid (0.111 g, 0.75 mmol)in tetrahydrofuran (2 mL) at 0° C. To the reaction solution was added 1Npotassium hydroxide (0.88 mL, 0.88 mmol) andTetrakis(triphenylphosphine)palladium(0) (0.058 g, 0.05 mmol). The vialwas purged with nitrogen and sealed. The sealed vial was heated in amicrowave reactor at 120° C. for 2 hr. The reaction was cooled to roomtemperature and diluted with 4 mL ethyl acetate. The organic layer wasseparated, dried over Na₂SO₄ and evaporated in vacuo. The crude oil waspurified by silica gel chromatography (5% ethyl acetate/95% hexanes→35%ethyl acetate/65% hexanes) to afford 0.123 g (87%) of the desired ether.Mass spec.: 591.22 (MNa)⁺; LC t_(r)=4.318 min. (Phenomenex-Luna 4.6×50mm S10, 10% MeOH/90% H₂O/0.1% TFA→90% MeOH/10% H₂O/0.1% TFA GradientTime=4 min, Flow rate=4 mL/min).

EXAMPLE 1

2-Methoxy-5-(3-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)phenyl)pyrimidine.tert-Butyl4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate(60. 0 mg, 0.11 mmol), 2-methoxy-5-pyridine boronic acid (72.0 mg, 0.47mmol), and tetrakis(triphenylphosphine) palladium(0) (17.1 mg, 0.011mmol) were combined in dry tetrahydrofuran (2 mL) in a microwave tubeand sealed. The mixture was flushed with nitrogen then 0.35 mL of a 1 Npotassium hydroxide aqueous solution was introduced. The mixture washeated at 120° C. for 1 h via microwave. After cooling to roomtemperature, the reaction mixture was concentrated and treated with atrifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h. Thesolvent was removed in vacuo and the resulting crude mixture passedthrough a strong cation exchange column. After washing the column withseveral volumes of methanol, the product was eluted by washing thecolumn with 2 M ammonia in methanol. Concentration and preparative HPLCafforded 21.0 mg (42%) of the desired compound as its TFA salt. ¹H-NMR(CDCl_(3,) 500 MHz) δ 8.57 (s, 2H), 7.54 (s, 1H), 7.25-7.31 (m, 8H),4.40 (s, 2H), 4.03 (s, 3H), 3.40 (s, 2H), 2.83-2.88 (m, 2H), 2.64-2.69(m, 2H), 2.10-2.18 (m, 2H), 1.77-1.86 (m, 2H). Mass spec.: 458.18 (MH)⁺.

EXAMPLE 2

4-(5-(3-(((4-Phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)phenyl)pyridin-2-yl)morpholine.¹H-NMR (CDCl_(3,) 500 MHz) δ 8.49 (d, J=2.1 Hz, 1H), 8.08 (dd, J=7.0,2.5 Hz, 1H), 7.72 (s, 1H), 7.61 (s, 1H), 7.35-7.38 (m, 3H), 7.26-7.30(m, 3H), 7.10 (d, J=9.5 Hz, 1H), 4.48 (s, 2H), 3.86-3.88 (m, 4H),3.71-3.73 (m, 4H), 3.42 (s, 2H), 3.28-3.31 (m, 2H), 2.86-2.90 (m, 2H),2.39-2.42 (m, 2H), 2.27-2.33 (m, 2H). Mass spec.: 512.37 (MH)⁺. Accuratemass spec.: m/z 512.2530 [MH]⁺, Δ=1.0 ppm.

EXAMPLE 3

5-(3-(((4-Phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)phenyl)picolinonitrile.¹H-NMR (CDCl_(3,) 500 MHz) δ 8.85 (s, 1H), 7.91 (dd, J=5.8, 2.4 Hz, 1H),7.80 (d, J=8.2 Hz, 1H), 7.67 (s, 1H), 7.47 (s, 1H), 7.43 (s, 1H), 7.38(d, J=1.2 Hz, 1H), 7.36 (s, 1H), 7.30-7.33 (m, 2H), 7.17-7.20 (m, 1H),4.48 (s, 2H), 3.49 (s, 2H), 2.91-2.94 (m, 2H), 2.74-2.79 (m, 2H),2.19-2.22 (m, 2H), 1.88-1.93 (m, 2H). Mass spec.: 452.22 (MH)⁺. Accuratemass spec.: m/z 452.1945 [MH]⁺, Δ=1.0 ppm.

EXAMPLE 4

3-Chloro-4-(3-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)phenyl)pyridine.¹H-NMR (CDCl_(3,) 500 MHz) δ 8.83 (s, 1H), 8.69 (d, J=5.5 Hz, 1H), 7.63(s, 1H), 7.55 (d, J=5.5 Hz, 1H), 7.50 (s, 1H), 7.47 (s, 1H), 7.29-7.41(m, 6H), 4.52 (s, 2H), 3.46 (s, 2H), 3.34-3.37 (m, 2H), 2.93-2.96 (m,2H), 2.45-2.48 (m, 2H), 2.20-2.26 (m, 2H). Mass spec.: 461.32 (MH)⁺.Accurate mass spec.: m/z 461.1596 [MH]⁺, Δ=2.5 ppm.

EXAMPLE 5

3-Methyl-4-(3-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)phenyl)pyridine.¹H-NMR (CDCl_(3,) 500 MHz) δ 8.74 (s, 1H), 8.72 (d, J=5.8 Hz, 1H), 7.72(d, J=5.8 Hz, 1H), 7.53 (s, 1H), 7.47 (s, 1H), 7.42 (s, 1H), 7.35-7.38(m, 2H), 7.24-7.31 (m, 3H), 4.54 (s, 2H), 3.47 (s, 2H), 3.34-3.37 (m,2H), 2.90-2.97 (m, 2H), 2.43 (s, 3H), 2.38-2.45 (m, 2H), 2.25-2.31 (m,2H). Mass spec.: 441.37 (MH)⁺. Accurate mass spec.: m/z 441.2167 [MH]⁺,Δ=3.0 ppm.

EXAMPLE 6

2-Methyl-4-(3-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)phenyl)pyridine.¹H-NMR (CDCl_(3,) 500 MHz) δ 8.81 (d, J=6.1 Hz, 1H), 7.86 (d, J=6.1 Hz,1H), 7.78-7.80 (m, 3H), 7.56 (s, 1H), 7.38-7.41 (m, 2H), 7.28-7.32 (m,3H), 4.54 (s, 2H), 3.47 (s, 2H), 3.33-3.35 (m, 2H), 2.90-2.96 (m, 2H),2.83 (s, 3H), 2.41-2.44 (m, 2H), 2.29-2.35 (m, 2H). Mass spec.: 441.37(MH)⁺. Accurate mass spec.: m/z 441.2165 [MH]⁺, Δ=2.6 ppm.

EXAMPLE 7

4-(3-(((4-Phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)phenyl)pyridine.¹H-NMR (CD₃OD, 500 MHz) δ 8.97 (s, 1H), 8.96 (s, 1H), 8.42 (s, 1H), 8.41(s, 1H), 8.17 (s, 1H), 7.98 (s, 1H), 7.75 (s, 1H), 7.41-7.51 (m, 2H),7.41-7.44 (m, 2H), 7.28-7.31 (m, 1H), 4.65 (s, 2H), 3.61 (s, 2H),3.36-3.38 (m, 2H), 2.95-3.00 (m, 2H), 2.56-2.59 (m, 2H), 2.24-2.29 (m,2H). ¹³C-NMR (CD₃OD, 126 MHz) δ 156.7, 142.4, 142.3, 141.9, 136.3, 132.2(q, J=33.6 Hz), 130.4, 129.1, 127.2, 126.9, 125.3, 124.0, 124.1 (q,J=271.6 Hz), 123.9, 79.6, 71.8, 41.1, 28.9. Mass spec.: 427.17 (MH)⁻.

EXAMPLE 8

3′-(((4-Phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CD₃OD, 500 MHz) δ 7.84-7.87 (m, 2H), 7.78-7.87 (m, 2H), 8.42 (s,1H), 7.67 (s, 1H), 7.55 (s, 1H), 7.48-7.50 (m, 2H), 7.40-7.43 (m, 2H),7.27-7.30 (m, 1H), 4.59 (s, 2H), 3.57 (s, 2H), 3.36-3.38 (m, 2H),2.94-2.99 (m, 2H), 2.55-2.58 (m, 2H), 2.20-2.26 (m, 2H). ¹³C-NMR (CD₃OD,126 MHz) δ 142.2, 141.4, 141.1, 140.7, 133.0, 131.6 (q, J=32.6 Hz),130.0, 129.0, 128.2, 127.2, 124.4 (q, J=272.6 Hz), 124.0, 123.0, 118.5.Mass spec.: 451.18(MH)⁺. TABLES 3 The following compounds were preparedby method A. Mass HPLC retention Spec. Example Structure Method time(MH+) 8

2 1.42 451.28 9

2 1.23 525.37 10

2 1.48 479.25 11

2 1.40 475.26 12

2 1.53 491.24 13

2 1.51 494.25 14

2 1.16 457.30 15

2 1.35 477.29 16

2 1.11 488.30 17

4 2.06 442.20 18

4 2.30 477.20 19

4 2.49 461.10 20

4 2.31 461.20 21

4 2.39 445.20 22

4 2.70 495.10 23

4 2.16 441.20 24

2 1.39 470.96 25

2 1.22 440.99 26

2 1.59 493.89 27

2 1.55 475.98 28

2 1.43 443.97 29

2 1.71 459.96 30

2 1.39 439.98 31

2 1.35 456.02 32

2 1.48 439.99 33

2 1.72 477.94 34

2 1.53 561.90 35

2 1.47 493.88 36

2 1.64 563.88 37

2 1.75 502.02 38

2 1.70 471.97 39

2 1.39 440.14 40

2 1.48 501.96 41

2 1.28 453.98 42

2 1.52 493.95 43

2 1.57 454.00 44

2 1.54 484.96 45

2 1.38 443.94 46

2 1.60 475.97 47

2 1.55 469.95 48

2 1.31 443.92 49

2 1.60 469.95 50

2 1.42 493.90 51

2 1.39 455.94 52

2 1.79 515.95 53

2 1.35 459.89 54

2 1.37 461.83 55

2 1.43 473.86 56

2 1.55 461.83 57

2 1.82 467.93 58

2 2.08 495.92 59

2 1.72 517.83 60

2 1.52 453.89 61

2 1.41 469.87 62

2 1.84 481.92 63

2 1.41 485.87 64

2 1.20 441.87 65

2 1.22 441.88 66

2 1.81 493.78 67

2 1.55 509.80 68

2 1.28 467.86 69

2 1.25 455.88 70

2 1.71 519.85 71

2 1.86 583.63 72

2 1.71 483.89 73

2 1.37 476.86 74

2 1.18 455.87 75

2 1.73 501.87 76

2 1.65 461.85 77

2 1.45 471.83 78

2 1.70 467.93 79

2 1.51 485.85 80

2 1.49 489.81 81

2 1.35 450.86 82

2 1.52 485.86 83

2 1.45 461.84 84

4 2.96 510.27 85

4 2.41 468.24 86

4 3.23 482.32 87

4 2.66 484.23 88

4 3.15 490.34 89

4 2.75 462.2 90

4 2.74 462.2 91

4 2.94 494.2 92

4 2.98 454.33 93

4 2.94 454.28 94

4 2.77 474.27 95

4 2.9 458.31 96

4 2.7 484.25 97

4 3.02 512.3 98

4 2.89 575.38 99

4 2.93 532.31 100

4 3.67 508.42 101

4 2.88 480.22 102

4 3 454.33 103

4 2.38 518.29 104

4 2.29 472.26 105

4 2.62 470.33 106

4 3.34 482.34 107

4 3.08 468.3 108

4 2.71 471.25 109

4 2.73 484.32 110

4 3.16 560.37 111

4 2.92 498.31 112

4 3.14 560.37 113

4 2.58 471.25 114

4 2.24 483.29 115

4 2.77 498.31 116

4 2.83 543.35 117

4 2.99 470.33 118

4 2.94 470.28 119

4 2.77 529.29 120

4 2.98 512.32 121

4 2.83 498.34 122

4 2.76 486.27 123

4 3.01 506.31 124

4 3.17 520.35 125

4 3.01 484.33 126

6 1.82 498.01 127

6 1.65 484.63 128

6 1.43 486.96 129

6 1 511.02 130

6 1.12 429.99 131

6 1.37 495.54 132

6 1.32 478.9 133

6 1.75 561.9

TABLE 4 Mass Synthetic HPLC retention Spec. Example Structure MethodMethod time (MH+) 134

A,D 1 2.54 474.12 135

A,D 1 2.40 470.30 136

A,D 1 2.40 458.15 137

A,D 1 2.49 492.05 138

A,D 1 2.47 458.53 139

A,D 1 2.46 476.18 140

A,D 1 2.39 488.90

EXAMPLE 141

2-(3-(((4-Phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)phenyl)pyridine.tert-Butyl4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate(50.0 mg, 0.094 mmol), 2-tri-n-butyl stanyl-pyridine (44.2 mg, 0.12mmol) and bis(triphenylphosphine) palladium(II) dichloride (3.0 mg,0.004 mmol) were combined in dry acetonitrile (2 mL) and heated at 150°C. for 1 h via microwave. After cooling to room temperature, thereaction mixture was concentrated and treated with a trifluoroaceticacid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent wasremoved in vacuo and the resulting crude mixture passed through a strongcation exchange column. After washing the column with several volumes ofmethanol, the product was eluted by washing the column with 2 M ammoniain methanol. Concentration and preparative HPLC afforded 21.0 mg (41%)as its TFA salt. ¹H-NMR (CDCl_(3,) 500 MHz) δ 8.71 (m, 1H), 8.14 (s,1H), 7.91 (s, 1H), 7.80 (m, 1H), 7.67 (d, J=7.9 Hz, 1H), 7.43 (s, 1H),7.31-7.38 (m, 4H), 7.27-7.29 (m, 1H), 7.19-7.22 (m, 1H), 4.47(s, 2H),3.47 (s, 2H), 2.90-2.95 (m, 2H), 2.73-2.79 (m, 2H), 2.18-2.21 (m, 2H),1.89-1.96 (m, 2H). Mass spec.: 427.24 (MH)⁺. Accurate mass spec.: m/z427.2015 [MH]⁺, Δ=4.2 ppm. TABLE 5 The following compounds were preparedby method B. HPLC retention time Mass spec. (t_(R), min) ExampleStructure (MH)⁺ (method 2) 142

415.93 1.67 143

432.86 1.46 144

427.93 1.44 145

497.87 1.45 146

429.93 1.2 147

425.92 1.67 148

445.9 1.71

EXAMPLE 149

4-Phenyl-4-((3-(trifluoromethyl)-5-(5-(trifluoromethyl)-1H-tetrazol-1-yl)benzyloxy)methyl)piperidine.tert-Butyl4-phenyl-4-((3-(trifluoromethyl)-5-(5-(trifluoromethyl)-1H-tetrazol-1-yl)benzyloxy)methyl)piperidine-1-carboxylate(46.0 mg, 0.078 mmol) was dissolved in a trifluoroacetic acid/methylenechloride mixture (1:1, 2 mL) and stirred under nitrogen for 1 h. Thesolvent was removed in vacuo and the resulting crude mixture passedthrough a strong cation exchange column. After washing the column withseveral volumes of methanol, the product was eluted by washing thecolumn with 2 M ammonia in methanol. Concentration afforded 29.0 mg(77%). ¹H-NMR (CDCl_(3,) 500 MHz) δ 7.61 (s, 1H), 7.58 (s, 1H), 7.3-7.33(m, 2H), 7.21-7.26 (m, 2H), 7.12 (s, 1H), 7.02-7.06 (m, 1H), 4.50 (s,2H), 3.48 (s, 2H), 2.89-2.93 (m, 2H), 2.72-2.77 (m, 2H), 2.19-2.22 (m,2H), 1.84-1.89 (m, 2H), ¹³C-NMR (CDCl₃, 125 MHz) δ 146.2 (q, J=42.2 Hz),146.1, 143.8, 143.5, 133.2, 132.7 (q, J=35.6 Hz), 128.3, 127.2, 126.6,126.5, 126.2, 122.8 (q, J=272.6 Hz), 121.1, 119.0, 116.8, 80.7, 71.1,42.6, 41.9, 33.4. Mass spec.: 486.18 (MH)⁻. Accurate mass spec.: m/z486.1739 [MH]⁺, Δ=2.1 ppm.

EXAMPLE 150

4-((2-Methoxy-5-(2-methyl-2H-tetrazol-5-yl)benzyloxy)methyl)-4-phenylpiperidine.tert-Butyl4-((2-methoxy-5-(2-methyl-2H-tetrazol-5-yl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate(28.0 mg, 0.057 mmol) was dissolved in a minimum amount of ethylacetate, followed by addition of 4 N hydrochloric acid (1 mL). Themixture was stirred under nitrogen for 1 h. After removing the solvents,the crude mixture was precipitated in diethyl ether and filtered toafford 16.0 g (73%) as its HCl salt. ¹H-NMR (CD₃OD, 500 MHz) δ 7.99-8.04(m, 2H), 7.50 (s, 1H), 7.49 (s, 1H), 7.41-7.45 (m, 3H), 7.10 (d, J=8.5Hz, 1H), 4.51 (s, 2H), 4.43 (s, 3H), 3.88 (s, 3H), 3.55 (s, 2H),3.35-3.37 (m, 2H), 2.94-3.09 (m, 2H), 2.45-2.54 (m, 2H), 2.31-2.37 (m,2H). ¹³C-NMR (CD₃OD, 76 MHz) δ 165.3, 159.2, 141.2, 129.0, 129.1, 127.7,127.6, 127.1, 127.0, 119.8, 110.9, 79.5, 68.0, 55.2, 41.3, 38.9, 28.8,28.3. Mass spec.: 394.25 (MH)⁺. Accurate mass spec.: m/z 394.2247 [MH]⁺,Δ=4.1 ppm.

EXAMPLE 151

4-((3-(1H-Tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine.tert-Butyl4-((3-(1H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate(30.0 mg, 0.058 mmol) was dissolved in a trifluoroacetic acid/methylenechloride mixture (1:1, 1 mL) and stirred under nitrogen for 1 h. Thesolvent was removed in vacuo and the resulting crude mixture passedthrough a strong cation exchange column. After washing the column withseveral volumes of methanol, the product was eluted by washing thecolumn with 2 M ammonia in methanol. Concentration afforded 11.0 mg(45%). LC/MS(HPLC method 3): t_(R)=1.89 min, 418.88 (MH)⁺.

EXAMPLE 152

3′-Chloro-5′-(((4-phenylpiperidin-4-yl)methoxy)methyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl_(3,) 500 MHz) δ 8.71 (m, 1H), 8.14 (s, 1H), 7.91 (s, 1H),7.80 (m, 1H), 7.67 (d, J=7.9 Hz, 1H), 7.43 (s, 1H), 7.31-7.38 (m, 4H),7.27-7.29 (m, 1H), 7.19-7.22 (m, 1H), 4.47 (s, 2H), 3.47 (s, 2H),2.90-2.95 (m, 2H), 2.73-2.79 (m, 2H), 2.18-2.21 (m, 2H), 1.89-1.96 (m,2H). Mass spec.: 417.27 (MH)⁺. Accurate mass spec.: m/z 417.1716 [MH]⁺,Δ=4.2 ppm.

EXAMPLE 153

4′-Fluoro-5-(((4-phenylpiperidin-4-yl)methoxy)methyl)biphenyl-3-carbonitrile.¹H-NMR (CDCl_(3,) 500 MHz) δ 7.65 (s, 1H), 7.41-7.44 (m, 3H), 7.32-7.37(m, 4H), 7.21-7.26 (m, 2H), 7.13-7.16 (m, 2H), 4.40 (s, 2H), 3.45 (s,2H), 2.91-2.95 (m, 2H), 2.74-2.79 (m, 2H), 2.19-2.22 (m, 2H), 1.88-1.93(m, 2H). ¹³C-NMR (CDCl₃, 126 MHz) δ 163.2 (d, J=248.6 Hz), 141.5, 141.0,135.1, 129.8, 129.5, 129.1, 128.9, 128.5, 127.3, 126.4, 118.7, 116.2,116.0, 113.1, 80.3, 72.0, 42.6, 41.9, 33.4. Mass spec.: 401.36 (MH)⁺.Accurate mass spec.: m/z 401.2046 [MH]⁺, Δ=4.2 ppm.

EXAMPLE 154

4′-Fluoro-5-(((4-phenylpiperidin-4-yl)methoxy)methyl)biphenyl-3-carboxamide.¹H-NMR (CDCl_(3,) 500 MHz) δ 7.95 (s, 1H), 7.68 (s, 1H), 7.47-7.50 (m,2H), 7.38 (s, 1H), 7.32-7.33 (m, 4H), 7.20-7.23 (m, 1H), 7.08-7.11 (m,2H), 4.47 (s, 2H), 3.41 (s, 2H), 3.02-3.04 (m, 2H), 2.70-2.75 (m, 2H),2.16-2.19 (m, 4H), ¹³C-NMR (CDCl₃, 126 MHz) δ 169.3, 163.8 (d, J=247.6Hz), 140.7, 139.8, 136.2, 134.3, 128.9, 128.3, 128.7, 127.2, 126.6,125.7, 124.5, 115.9, 115.7, 79.7, 72.6, 50.7, 41.9, 31.6. Mass spec.:419.37 (MH)⁻. Accurate mass spec.: m/z 419.2133 [MH]⁺, Δ=0.4 ppm.

EXAMPLE 155

4′-Fluoro-5-(((4-phenylpiperidin-4-yl)methoxy)methyl)biphenyl-3-ol.¹H-NMR (CDCl_(3,) 500 MHz) δ 7.51-7.54 (m, 2H), 7.46-7.48 (m, 2H),7.40-7.43 (m, 2H), 7.29-7.31 (m, 1H), 7.14-7.18 (m, 2H), 6.91-6.92 (m,1H), 6.86 (s, 1H), 6.69 (m, 1H), 4.41 (s, 2H), 3.49 (s, 2H), 3.31 (m,2H), 2.93-2.98 (m, 2H), 2.49-2.52 (m, 2H), 2.21-2.27 (m, 2H). Massspec.: 392.36 (MH)⁺. Accurate mass spec.: m/z 392.2009 [MH]⁺, Δ=4.3 ppm.

EXAMPLE 156

3′-(((4-(2-cyano-4-fluorophenyl)piperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl_(3,) 400 MHz) δ 7.73 (d, J=8.8 Hz, 2H), 7.69 (s, 1H), 7.60(d, J=8.4 Hz, 2H), 7.25-7.43 (m, 5H), 4.51 (s, 2H), 3.81 (s, 2H), 3.27m, 2H), 2.95 (m, 2H), 2.65 (m, 2H), 2.29 (m, 2H). Mass spec.: 494.16(M+H), HPLC (method 5) 3.06 min

EXAMPLE 157

3′-(((4-(5-fluorobiphenyl-2-yl)piperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl_(3,) 400 MHz) δ 7.73 (m, 3H), 7.58 (d, J=8.6 Hz, 2H), 7.43(d, J=8.3 Hz, 2H), 7.31 (M, 1H), 7.18-7.28 (M, 3H), 7.04 (m, 1H), 6.90(d, 6.9 Hz, 2H), 6.73 (m, 1H), 4.53 (s, 2H), 3.47 (s, 2H), 3.04 (m, 2H),2.75 (m, 2H), 2.09 (m, 2H), 1.78 (m, 2H). Mass spec. : 545.2 (M+H), HPLC(method 5) 3.57 min.

EXAMPLE 158

3′-(((4-(3-Chlorophenyl)piperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl₃, 500 MHz) δ ppm 7.75 (m, 2H), 7.68 (s, 1H), 7.61 (s, 1H),7.44 (s, 1H), 7.37 (s, 1H), 7.21-7.30 (m, 4H), 7.16 (m, 1H), 4.48 (s,2H), 3.43 (s, 2H), 3.32 (m, 2H), 2.88 (m, 2H), 2.42 (m, 2H), 2.21 (m,2H). Mass spec.: 485.17 (MH)⁺.

EXAMPLE 159

3′-(((4-(3,4-Difluorophenyl)piperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl₃, 500 MHz) δ ppm 7.75 (m, 2H), 7.68 (s, 1H), 7.61 (m, 2H),7.44 (s, 1H), 7.37 (s, 1H), 6.99-7.17 (br m, 3H), 4.48 (s, 2H), 3.42 (m,2H), 3.09 (m, 2H), 2.80 (m, 2H), 2.20 (m, 2H), 2.05 (m, 2H). Mass spec.:487.17 (MH)⁺.

EXAMPLE 160

3′-(((4-(4-Bromophenyl)piperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl₃, 500 MHz) δ ppm 7.77 (m, 2H), 7.67 (s, 1H), 7.59 (m, 2H),7.43 (m, 4H), 7.22 (m, 2H), 4.46 (s, 2H), 3.44 (s, 2H), 2.98 (m, 2H),2.75 (m, 2H), 2.17 (m, 2H), 1.94 (m, 2H). Mass spec.: 531.11 (MH)⁺.

EXAMPLE 161

3′-(((4-(3-Bromophenyl)piperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl₃, 500 MHz) δ ppm 7.75 (m, 2H), 7.67 (s, 1H), 7.60 (m, 2H),7.48 (s, 1H), 7.41 (m, 2H), 7.15-7.34 (m, 3H), 4.46 (s, 2H), 3.45 (s,2H), 2.97 (m, 2H), 2.76 (m, 2H), 2.17 (m, 2H), 1.96 (m, 2H). Mass spec.:531.11 (MH)⁺.

EXAMPLE 162

3′-(((4-(3-Cyanophenyl)piperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl₃, 500 MHz) δ ppm 7.76 (m, 2H), 7.68 (s, 1H), 7.61 (m, 2H),7.57-7.61 (m, 2H), 7.49 (m, 1H), 7.39-7.44 (m, 2H), 7.34 (s, 1H), 4.47(s, 2H), 3.46 (s, 2H), 3.03 (m, 2H), 2.76 (m, 2H), 2.22 (m, 2H), 2.03(m, 2H). Mass spec.: 476.18 (MH)⁺.

EXAMPLE 163

(S)-3′-(1-((4-Phenylpiperidin-4-yl)methoxy)ethyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H NMR (500 MHz, CDCl₃) δ ppm 7.73 (d, J=8.6 Hz, 2H), 7.64 (s, 1H), 7.55(d, J=8.6 Hz, 2H), 7.38 (s, 2H), 7.20-7.35 (m, 4H), 7.16 (m, 1H), 4.29(q, J=6.4 Hz, 1H), 3.46 (s, 1H), 3.33 (d, J=9.2 Hz, 1H), 3.25 (d, J=8.9Hz, 1H), 2.90 (m, 2H), 2.73 (m, 2H), 2.00-2.25 (m, 2H), 1.80-1.99 (m,2H), 1.35 (d, J=6.4 Hz, 3H). Mass spec.: 465.20 (MH)⁺. Accurate massspec.: m/z 465.2136 [MH]⁺, Δ=3.8 ppm.

EXAMPLE 164

4-(((4′-Fluoro-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(4-fluorophenyl)piperidine.¹H-NMR (CDCl₃, 500 MHz) δ 7.63 (s, 1H), 7.46 (m, 2H), 7.40 (s, 1H),7.28-7.37 (m, 3H), 7.15 (m, 2H), 7.00 (m, 2H), 4.45 (s, 2H), 3.44 (s,2H), 2.91 (m, 2H), 2.74 (m, 2H), 2.14 (m, 2H), 1.91 (bs, 1H), 1.89 (m,2H); ¹³C NMR (126 MHz, CDCl₃) δ ppm 164.0, 162.3, 162.0, 160.4, 141.2,140.5, 139.9, 135.8, 131.4 (q, J=33 Hz), 128.9 (m), 128.8 (m), 124.1 (q,J=273 Hz), 122.8 (q, J=3.8 Hz), 122.6 (q, J=3.8 Hz), 116.1, 115.9,115.1, 115.0, 79.8, 72.4, 42.6, 41.5, 33.8. Mass spec.: 462.20 (MH)⁺.Accurate mass spec.: m/z 462.1875 [MH]⁺, Δ=4.0 ppm.

EXAMPLE 165

(±)-3′-Fluoro-5′-(1-((4-phenylpiperidin-4-yl)methoxy)ethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl₃, 500 MHz) δ 7.71 (d, J=8.2 Hz, 2H), 7.54 (d, J=8.2 Hz,2H), 7.31 (m, 4H), 7.19 (m, 1H), 7.10 (m, 1H), 7.02 (s, 1H), 6.78 (m,1H), 4.21 (q, J=6.4 Hz, 1H), 3.28 (q_(AB), J_(AB)=8.9 Hz, 2H), 2.90 (m,2H), 2.74 (m, 2H), 2.19 (m, 1H), 2.12 (m, 1H), 1.91 (m, 2H), 1.83 (bs,1H), 1.32 (d, J=6.4 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ ppm 164.4,162.4, 148.3, 148.2, 144.4, 144.3, 141.3, 141.2, 132.7, 128.3, 127.8,127.4, 126.1, 120.3, 118.7, 113.2, 113.1, 113.0, 112.8, 111.7, 78.4,77.8, 50.8, 42.8, 42.7, 41.9, 33.6, 33.3, 24.0. Mass spec.: 415.32(MH)⁺. Accurate mass spec.: m/z 415.2167 [MH]⁺, Δ=4.5 ppm.

EXAMPLE 166

(±)-3′-Chloro-5′-(1-((4-phenylpiperidin-4-yl)methoxy)ethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl₃, 500 MHz) δ 7.70 (d, J=8.6 Hz, 2H), 7.52 (d, J=8.6 Hz,2H), 7.38 (m, 1H), 7.25-7.42 (m, 4H), 7.17 (m, 1H), 7.09 (s, 1H), 7.06(s, 1H), 4.19 (q, J=6.4 Hz, 1H), 3.27 (q_(AB), J_(AB)=8.9, 2H), 2.89 (m,2H), 2.72 (m, 2H), 2.19 (m, 1H), 2.10 (m, 1H), 1.90 (m, 2H), 1.78 (bs,1H), 1.31 (d, J=6.4 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ ppm 147.5,144.2, 141.0, 135.0, 132.7, 128.3, 127.9, 127.4, 126.4, 126.13, 126.10,123.0, 118.8, 111.6, 78.4, 77.2, 42.79, 42.75, 41.8, 33.7, 33.3, 24.2.Mass spec.: 431.30 (MH)⁺. Accurate mass spec.: m/z 431.1899 [MH]⁺, Δ=2.0ppm.

EXAMPLE 167

5-(((4-Phenylpiperidin-4-yl)methoxy)methyl)biphenyl-3,4′-dicarbonitrile.¹H-NMR (CDCl_(3,) 500 MHz) δ 7.74-7.76 (m, 2H), 7.69 (m, 1H), 7.55-7.57(m, 2H), 7.47 (m, 1H), 7.32-7.37 (m, 5H), 7.20-7.23 (m, 1H), 4.43 (s,2H), 3.47 (s, 2H), 2.92-2.94 (m, 2H), 2.74-2.79 (m, 2H), 2.19-2.22 (m,2H), 1.88-1.93 (m, 2H). Mass spec.: 408.23 (MH)⁺. Accurate mass spec.:m/z 408.2072 [MH]⁺, Δ=0.9 ppm.

EXAMPLE 168

3′-Methyl-5′-(((4-phenylpiperidin-4-yl)methoxy)methyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl_(3,) 500 MHz) δ 7.69-7.70 (m, 2H), 7.58-7.59 (m, 2H),7.29-7.37 (m, 4H), 7.19-7.25 (m, 2H), 7.10 (m, 1H), 6.95 (m, 1H), 4.39(s, 2H), 3.43 (s, 2H), 2.92-2.96 (m, 2H), 2.73-2.78 (m, 2H), 2.36 (s,3H), 2.18-2.21 (m, 2H), 1.91-1.97 (m, 2H). Mass spec.: 397.40 (MH)⁺.Accurate mass spec.: m/z 397.2296 [MH]⁺, Δ=4.1 ppm.

EXAMPLE 169

4-(((3′,5′-Difluoro-4′-methoxy-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine.¹H-NMR (CD₃OD, 500 MHz) δ 7.76 (s, 1H), 7.56 (s, 1H), 7.48-7.49 (m, 3H),7.41-7.44 (m, 2H), 7.25-7.31 (m, 3H), 4.56 (s, 2H), 4.04 (s, 3H), 3.35(s, 2H), 3.35-3.36 (m, 2H), 2.94-2.99 (m, 2H), 2.55-2.58 (m, 2H),2.18-2.24 (m, 2H). Mass spec.: 492.04 (MH)⁺. Accurate mass spec.: m/z492.1976 [MH]⁺, Δ=2.9 ppm.

EXAMPLE 170

4-(((2′,5′-Difluoro-4′-methoxy-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine.¹H-NMR (CDCl_(3,) 500 MHz) δ 7.57 (s, 1H), 7.23-7.33 (m, 6H), 7.15-7.18(m, 1H), 7.02-7.09 (m, 1H), 6.73-6.80 (m, 1H), 4.39 (s, 2H), 3.89 (s,3H), 3.42 (s, 2H), 2.88-2.94 (m, 2H), 2.68-2.77 (m, 2H), 2.17-2.21 (m,2H), 1.89-1.95 (m, 2H). Mass spec.: 492.20 (MH)⁺. Accurate mass spec.:m/z 492.1978 [MH]⁺, Δ=3.3 ppm.

EXAMPLE 171

3-Methoxy-3′-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.LC/MS: t_(R)=2.59 min, 481.18 (MH)⁺. Accurate mass spec.: m/z 481.2103[MH]⁺, Δ=0.4 ppm. (Phenomenex C18 4.6×50 mm, 10% MeOH/90% H₂O/0.1%TFA→90% MeOH/10% H₂O/0.1% TFA, Gradient time=4 min., Flow rate=4mL/min.).

EXAMPLE 172

2,5-Difluoro-3′-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.LC/MS: t_(R)=2.61 min, 487.15 (MH)⁺. Accurate mass spec.: m/z487.1801[MH]⁺, Δ=1.6 ppm. (Phenomenex C18 4.6×50 mm, 10% MeOH/90%H₂O/0.1% TFA→90% MeOH/10% H₂O/0.1% TFA, Gradient time=4 min., Flowrate=4 mL/min.).

EXAMPLE 173

3′-(((4-(2-bromo-4-fluorophenyl)piperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.A solution of tert-butyl4-(2-bromo-4-fluorophenyl)-4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)piperidine-1-carboxylate(50 mg, 0.077 mmol) in dichloromethane (0.5 mL) and trifluoroacetic acid(2 mL) was stirred at ambient temperature for 3 hours. The reaction wasevaporated to dryness and the resulting residue was purified bychromatography on silica with gradient of methanol/dichloromethane of 2%to 10%. The product3′-(((4-(2-bromo-4-fluorophenyl)piperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile(29 mg, 69% yield) was obtained as a clear oil. ¹H-NMR (CDCl_(3,) 400MHz) δ 7.74 (d, J=6.8 Hz, 2H), 7.68 (s, 1H), 7.58 (d, J=6.7 Hz, 2H),7.36 (s, 1H), 7.33 (s, 1H), 7.22-7.33 (m, 2H), 7.03 (m, 1H), 4.49 (s,2H), 3.88 (s, 2H), 3.25 (m, 2H), 2.94 (m, 2H), 2.85 (m, 2H), 2.23 (m,2H). Mass spec.: 547.12 (M+H), HPLC (method 5) 3.37 min.

EXAMPLE 174

4′-Cyano-N,N-dimethyl-5-(((4-phenylpiperidin-4-yl)methoxy)methyl)biphenyl-3-carboxamide.tert-Butyl4-((3-bromo-5-(dimethylcarbamoyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate(41.2 mg, 0.08 mmol), 4-cyanophenylboronic acid (34.3 mg, 0.23 mmol),and tetrakis(triphenylphosphine) palladium(0) (12.1 mg, 0.01 mmol) werecombined in dry tetrahydrofuran (3 mL) in a microwave tube and sealed.After flushing with nitrogen, 0.28 mL of a 1 N potassium hydroxideaqueous solution was introduced. The mixture was heated at 120° C. for 1h via microwave. After cooling to room temperature, the reaction mixturewas concentrated and treated with a trifluoroacetic acid/methylenechloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuoand the resulting crude mixture passed through a strong cation exchangecolumn. After washing the column with several volumes of methanol, theproduct was eluted by washing the column with 2 M ammonia in methanoland concentrated to afford 29 mg (66%). ¹H-NMR (CD₃OD, 500 MHz) δ7.81-7.84 (m, 2H), 7.76 (s, 1H), 7.74 (s, 1H), 7.59 (s, 1H), 7.49 (s,1H), 7.42-7.44 (m, 2H), 7.32-7.35 (m, 2H), 7.17-7.22 (m, 2H), 4.51 (s,2H), 3.52 (s, 2H), 3.15 (s, 3H), 2.99 (s, 3H), 2.88-2.95 (m, 2H),2.67-2.72 (m, 2H), 2.24-2.27 (m, 2H), 1.91-1.97 (m, 2H). ¹³C-NMR NMR(CD₃OD, 126 MHz) δ 172.2, 144.9, 144.2, 140.9, 139.9, 137.3, 132.9,128.4, 128.1, 127.4, 127.2, 126.2, 125.7, 124.7, 118.7, 111.5, 79.9,72.2, 42.1, 41.8, 39.1, 34.7, 32.7. Mass spec.: 454.31 (MH)⁻. Accuratemass spec.: m/z 454.2496 [MH]⁺, Δ=0.3 ppm.

EXAMPLE 175

3′-(((4-Phenylpiperidin-4-yl)methoxy)methyl)-5′-(piperidine-1-carbonyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl_(3,) 500 MHz) δ 7.73 (s, 1H), 7.71 (s, 1H), 7.59 (s, 1H),7.51 (s, 1H), 7.45 (s, 1H), 7.35-7.36 (m, 2H), 7.31-7.32 (m, 3H),7.17-7.20 (m, 2H), 4.43 (s, 2H), 3.71-3.73 (m, 2H), 3.45 (s, 2H),3.31-3.33 (m, 2H), 2.90-2.95 (m, 2H), 2.73-2.78 (m, 2H), 2.16-2.20 (m,2H), 1.89-1.95 (m, 2H), 1.68 (m, 4H), 1.49 (m, 2H). ¹³C-NMR (CDCl₃, 126MHz) δ 169.7, 144.8, 144.0, 140.3, 139.6, 137.6, 132.7, 128.4, 127.9,127.3, 126.7, 126.2, 125.5, 124.7, 118.7, 111.5, 80.0, 77.7, 72.6, 50.9,42.6, 41.9, 33.3, 27.7. Mass spec.: 494.47 (MH)⁺. Accurate mass spec.:m/z 494.2809 [MH]⁺, Δ=0.3 ppm.

EXAMPLE 176

3′-(Morpholine-4-carbonyl)-5′-(((4-phenylpiperidin-4-yl)methoxy)methyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl_(3,) 500 MHz) δ 7.73 (s, 1H), 7.71 (s, 1H), 7.59 (s, 1H),7.57 (s, 1H), 7.47 (s, 1H), 7.29-7.37 (m, 5H), 7.17-7.20 (m, 1H), 7.16(s, 1H), 4.44 (s, 2H), 3.41-3.78 (m, 8H), 3.46 (s, 2H), 2.89-2.93 (m,2H), 2.72-2.77 (m, 2H), 2.16-2.19 (m, 2H), 1.88-1.93 (m, 2H). ¹³C-NMR(CDCl₃, 126 MHz) δ 169.8, 144.6, 144.2, 140.6, 139.9, 136.5, 132.7,128.4, 127.9, 127.3, 127.1, 126.2, 125.6, 125.0, 118.7, 111.7, 80.2,77.7, 72.5, 67.0, 42.7, 42.0, 33.5. Mass spec.: 496.46 (MH)⁺.

EXAMPLE 177

4-(((4′-Fluoro-5-methoxybiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine.tert-Butyl4-(((4′-fluoro-5-hydroxybiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate(42.4 mg, 0.09 mmol), iodomethane (11 μL, 0.17 mmol) and potassiumcarbonate (23.5 mg, 0.17 mmol) were combined in dimethylformamide (2mL). After stirring at room temperature for 16 h, the solvent wasremoved in vacuo and the crude product dissolved in ethyl acetate,washed with water (2×), then brine (2×), dried over sodium sulfate, andconcentrated to afford a precipitate which was treated with atrifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h. Thesolvent was removed in vacuo and the resulting crude mixture passedthrough a strong cation exchange column. After washing the column withseveral volumes of methanol, the product was eluted by washing thecolumn with 2 M ammonia in methanol. Concentration and preparative HPLCafforded 22 mg (61%) as its trifluoroacetic acid salt. ¹H-NMR (CDCl_(3,)300 MHz) δ 7.53-7.58 (m, 2H), 7.39-7.48 (m, 4H), 7.30-7.32 (m, 1H),7.14-7.20 (m, 2H), 7.00-7.01 (m, 1H), 6.96 (s, 1H), 6.75 (s, 1H), 4.45(s, 2H), 3.82 (s, 3H), 3.50 (s, 2H), 3.29-3.31 (m, 2H), 2.89-3.00 (m,2H), 2.49-2.54 (m, 2H), 2.18-2.28 (m, 2H). Mass spec.: 406.37 (MH)⁺.Accurate mass spec.: m/z 406.2173 [MH]⁺, Δ=2.3 ppm.

EXAMPLE 178

4-(((2′,3′-Difluoro-4′-methoxy-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine.tert-Butyl4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate(150 mg, 0.28 mmol), 2,3-difluoro-4-methoxyphenylboronic acid (139 mg,0.84 mmol), and tetrakis(triphenylphosphine) palladium(0) (33 mg, 0.03mmol) were combined in dry tetrahydrofuran (3 mL) in a microwave tubeand sealed. After flushing with nitrogen, 1.0 mL of a 1 N potassiumhydroxide aqueous solution was introduced. The mixture was heated at120° C. for 1 h via microwave. After cooling to room temperature, thereaction mixture was concentrated and treated with a trifluoroaceticacid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent wasremoved in vacuo and the resulting crude mixture passed through a strongcation exchange column. After washing the column with several volumes ofmethanol, the product was eluted by washing the column with 2 M ammoniain methanol and concentrated to afford 45 mg (33%). ¹H-NMR (CDCl_(3,)500 MHz) δ 7.57 (s, 1H), 7.26-7.38 (m, 6H), 7.13-7.17 (m, 1H), 7.00-7.06(m, 1H), 6.77-6.83 (m, 1H), 4.41 (s, 2H), 3.93 (s, 3H), 3.44 (s, 2H),2.84-2.92 (m, 2H), 2.68-2.77 (m, 2H), 2.13-2.18 (m, 2H), 1.83-1.92 (m,2H). Mass spec.: 492.01 (MH)⁺. Accurate mass spec.: m/z 492.1978 [MH]⁺,Δ=3.3 ppm.

EXAMPLE 179

4-((3-(2-Methyl-2H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine.tert-Butyl4-((3-(2-methyl-2H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate(48.0 mg, 0.09 mmol) was dissolved in a minimum amount of ethyl acetate,followed by addition of 4 N hydrochloric acid (1 mL). The mixture wasstirred under nitrogen for 1 h. After removing the solvents, the crudemixture was precipitated in diethyl ether and filtered to afford 26.0 mg(67%) as a white powder. ¹H-NMR (CDCl_(3,) 300 MHz) δ 8.23 (s, 1H), 8.10(s, 1H), 7.40 (s, 1H), 7.28-7.36 (m, 4H), 7.20 (m, 1H), 4.41 (s, 2H),4.38 (s, 3H), 3.44 (s, 2H), 2.86-2.93 (m, 2H), 2.69-2.77 (m, 2H),2.16-2.20 (m, 2H), 1.83-1.96 (m, 2H). ¹³C-NMR (CDCl₃, 76 MHz) δ 164.0,143.4, 141.0, 131.4 (q, J=32.8 Hz), 128.3, 128.0, 127.0, 126.1, 135.5,124.0 (q, J=213.8 Hz), 122.6, 121.9, 79.9, 72.0, 42.3, 41.7, 39.5, 32.9.Mass spec.: 432.20 (MH)⁻. Accurate mass spec.: m/z 432.1994 [MH]⁺, Δ=4.0ppm.

EXAMPLE 180

4-((3-(1-Methyl-1H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine.tert-Butyl4-((3-(1-methyl-1H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate(7.0 mg, 0.01 mmol) was dissolved in a minimum amount of ethyl acetate,followed by addition of 4 N hydrochloric acid (0.5 mL). The mixture wasstirred under nitrogen for 1 h. After removing the solvents, the crudemixture was precipitated in diethyl ether and filtered to afford 4.0 mg(88%). ¹H-NMR (CDCl_(3,) 500 MHz) δ 7.86 (s, 1H), 7.57 (s, 1H), 7.48 (s,1H), 7.34 (s, 1H), 7.33 (s, 1H), 7.27-7.29 (m, 2H), 7.20 (m, 1H), 4.49(s, 2H), 4.06 (s, 3H), 3.48 (s, 2H), 2.93-2.96 (m, 2H), 2.74-2.77 (m,2H), 2.20-2.22 (m, 2H), 1.89-1.94 (m, 2H). Mass spec.: 432.20 (MH)⁺.Accurate mass spec.: m/z 432.1994 [MH]⁺, Δ=4.4 ppm.

EXAMPLE 181

4-((3-(5-Methyl-1H-tetrazol-1-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine.tert-Butyl4-((3-(5-methyl-1H-tetrazol-1-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate(40.0 mg, 0.08 mmol) was dissolved in a minimum amount of ethyl acetate,followed by addition of 4 N hydrochloric acid (1.5 mL). The mixture wasstirred under nitrogen for 1 h. After removing the solvents, the crudemixture was precipitated in diethyl ether and filtered to afford 30.0 mg(93%) as a white powder. ¹H-NMR (CDCl_(3,) 500 MHz) δ 7.58 (s, 1H), 7.53(s, 1H), 7.31-7.35 (m, 3H), 7.22-7.26 (m, 1H), 7.08-7.11 (m, 2H), 4.49(s, 2H), 3.43 (s, 2H), 2.86-2.90 (m, 2H), 2.71-2.75 (m, 2H), 2.52 (s,3H), 2.17-2.20 (m, 2H), 1.84-1.87 (m, 2H). ¹³C-NMR (CDCl₃, 126 MHz) δ151.5, 143.9, 143.1, 134.5, 136.6 (q, J=33.6 Hz), 128.7, 128.3, 127.2,126.3, 127.7, 125.1 (q, J=272.6 Hz), 120.4, 80.6, 71.3, 42.6, 41.9,33.6, 33.3. Mass spec.: 432.22 (MH)⁺.

EXAMPLE 182

4-((2-Methoxy-5-(5-methyl-1H-tetrazol-1-yl)benzyloxy)methyl)-4-phenylpiperidine.tert-Butyl4-((2-methoxy-5-(5-methyl-1H-tetrazol-1-yl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate(30.0 mg, 0.06 mmol) was dissolved in a minimum amount of ethyl acetate,followed by addition of 4 N hydrochloric acid (1 mL). The mixture wasstirred under nitrogen for 1 h. After removing the solvents, the crudemixture was precipitated in diethyl ether and filtered to afford 18.0 mg(76%) as a white powder. ¹H-NMR (CDCl_(3,) 500 MHZ) δ 7.32 (s, 1H), 7.30(s, 1H), 7.18-7.25 (m, 3H), 7.04-7.07 (m, 1H), 6.91 (d, J=8.9 Hz, 1H),6.81 (m, 1H), 4.46 (s, 2H), 3.85 (s, 3H), 3.48 (s, 2H), 2.88-2.93 (m,2H), 2.72-2.76 (m, 2H), 2.41 (s, 3H), 2.18 (m, 2H), 1.85-1.90 (m, 2H).¹³C-NMR (CDCl₃, 126 MHz) δ 157.5, 151.7, 144.2, 129.6, 128.2, 127.2,126.6, 126.1, 124.6, 123.6, 110.5, 80.5, 67.0, 55.8, 42.7, 41.8, 33.6,9.6. Mass spec.: 394.22 (MH)⁺. Accurate mass spec.: m/z 394.2222 [MH]⁺,Δ=4.1 ppm.

EXAMPLE 183

4-(4-Methoxy-3-(((4-phenylpiperidin-4-yl)methoxy)methyl)phenyl)pyridine.tert-Butyl4-((2-methoxy-5-(pyridin-4-yl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate(26 mg, 0.053 mmol) was dissolved in trifluoroacetic acid (33% indichloromethane, 4 mL) and stirred for 1 h. The reaction wasconcentrated and purified by column chromatography (5%methanol/dichloromethane/2% trimethylamine in ethanol→10%methanol/dichloromethane/2% trimethylamine in ethanol) to give 30.7 mg(quant.) as a colorless oil. The product was tainted with trimethylamine2,2,2-trifluoroacetate. ¹H NMR (500 MHz, CDCl₃) δ ppm 13.28 (bs, 2H),9.55 (m, 2H), 8.71 (d, J=5.2 Hz, 2H), 7.79 (d, J=5.2 Hz, 2H), 7.60 (m,2H), 7.34 (m, 4H), 7.26 (m, 1H), 6.94 (d, J=8.6, 1H), 4.48 (s, 2H), 3.84(s, 3H), 3.49 (s, 2H), 3.31 (m, 2H); ¹³C NMR (126 MHz, CDCl₃) δ ppm159.1, 154.0, 144.0, 140.5, 129.2, 128.6, 127.7, 127.4, 127.2, 126.9,122.5, 110.8, 80.0, 67.5, 55.7, 41.2, 40.6. Mass spec.: 389.33 (MH)⁺.Accurate mass spec.: m/z 389.2228 [MH]⁺, Δ=0.3 ppm.

EXAMPLE 184

5-(4-Methoxy-3-(((4-phenylpiperidin-4-yl)methoxy)methyl)phenyl)picolinonitrile.tert-Butyl4-((5-(6-cyanopyridin-3-yl)-2-methoxybenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate(46 mg, 0.090 mmol) was dissolved in trifluoroacetic acid (33% indichloromethane, 4 mL) and stirred for 1 h. The reaction wasconcentrated and purified by column chromatography (5%methanol/dichloromethane/2% trimethylamine in ethanol→10%methanol/dichloromethane/2% trimethylamine in ethanol) to give 43.6 mg(quant.) as a colorless oil. The product was tainted with trimethylamine2,2,2-trifluoroacetate. ¹H NMR (500 MHz, CDCl₃) δ ppm 9.47 (bs, 1H),9.25 (bs, 1H), 8.79 (m, 1H), 7.84 (m, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.44(dd, J=8.5, 2.1, 1H), 7.33 (m, 5H), 7.25 (m, 1H), 6.91 (d, J=8.5 Hz,1H), 4.47 (s, 2H), 3.82 (s, 3H), 3.48 (s, 2H), 3.27 (bd, 2H), 2.90 (m,2H), 2.44 (m, 2H), 2.26 (m, 2H); ¹³C NMR (126 MHz, CDCl₃) δ ppm 157.8,149.3, 140.5, 139.5, 134.3, 131.4, 129.1, 128.5, 128.2, 127.9, 127.2,126.8, 126.6, 117.7, 110.8, 79.9, 67.7, 55.6, 41.1, 40.6, 29.1. Massspec.: 414.19 (MH)⁺. Accurate mass spec.: m/z 414.2188 [MH]⁺, Δ=1.6 ppm.

EXAMPLE 185

4′-Methoxy-3′-(((4-phenylpiperidin-4-yl)methoxy)methyl)biphenyl-4-carbonitrile.tert-Butyl4-(((4′-cyano-4-methoxybiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate(47 mg, 0.092 mmol) was dissolved in dichloromethane (2 mL) andtrifluoroacetic acid (1 mL). The reaction was stirred for 45 min andconcentrated. The residue was dissolved in methanol and loaded onto anstrong cation exchange cartridge. The cartridge was flushed with plentyof methanol which was discarded. The product was then eluted using 2 Mammonia in methanol. The solvent was evaporated to give 34 mg (90%) as acolorless oil. Retention time: 2.20 min. (Phenomenex C18 3.0×50 mm, 10%MeOH/90% H₂O/0.1% TFA→90% MeOH/10% H₂O/0.1% TFA, Gradient time=3 min.,Flow rate=4 mL/min.) Mass spec.: 413.39 (MH)⁺. Accurate mass spec.: m/z413.2245 [MH]⁺, Δ=3.9 ppm.

EXAMPLE 186

3′-(((4-(4-Fluorophenyl)piperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.tert-Butyl4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate(47.0 mg, 0.09 mmol) was treated with a trifluoroacetic acid/methylenechloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuoand the resulting crude mixture passed through a strong cation exchangecolumn. After washing the column with several volumes of methanol, theproduct was eluted by washing the column with 2 M ammonia in methanol.The solvents were removed in vacuo to afford 37.0 mg (92%). ¹H-NMR(CDCl_(3,) 500 MHz) δ 7.75 (s, 1H), 7.73 (s, 1H), 7.66 (s, 1H), 7.58 (s,1H), 7.57 (s, 1H), 7.41 (s, 1H), 7.40 s, 1H), 7.30-7.33 (m, 2H),6.96-7.00 (m, 2H), 4.46 (s, 2H), 3.44 (s, 2H), 2.87-2.91 (m, 2H),2.70-2.75 (m, 2H), 2.11-2.14 (m, 2H), 1.87-1.90 (m, 2H). Mass spec.:469.33 (MH)⁺.

EXAMPLE 187

3′-(((1-Methyl-4-phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.3′-(((4-Phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile(18.3 mg, 0.04 mmol) and formaldehyde (37 wt. % solution in water, 86.4μL, 3.22 mmol) were combined in acetonitrile (1.0 mL) and cooled to 0°C. The reaction was treated with sodium cyanoborohydride (12.6 mg, 0.2mmol) and a few drops of acetic acid. The reaction was stirred at 0° C.for 30 min and at room temperature for 1 h. The solvent was removed invacuo and the resulting crude mixture passed through a strong cationexchange column. After washing the column with several volumes ofmethanol, the product was eluted by washing the column with 2 M ammoniain methanol. The solvents were evaporated to afford 12.1 mg (65%).¹H-NMR (CDCl_(3,) 500 MHz) δ 7.74-7.76 (m, 2H), 7.66 (s, 1H), 7.58-7.60(m, 2H), 7.44 (s, 1H), 7.41 (s, 1H), 7.36-7.38 (m, 2H), 7.30-7.33 (m,2H), 7.18-7.21 (m, 1H), 4.45 (s, 2H), 3.48 (s, 2H), 2.58-2.60 (m, 2H),2.17-2.28 (m, 4H), 2.21 (s, 3H), 1.98-2.08 (m, 2H). Mass spec.: 465.11(MH)⁺.

EXAMPLE 188

4-(3-(((1-Methyl-4-phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)phenyl)pyridine.¹H-NMR (CDCl_(3,) 500 MHz) δ 8.96 (s, 1H), 8.95 (s, 1H), 8.01 (s, 1H),8.00 (s, 1H), 7.83 (s, 1H), 7.69 (s, 1H), 7.55 (s, 1H), 7.42-7.45 (m,2H), 7.33-7.36 (m, 3H), 4.55 (s, 2H), 3.55-3.57 (m, 2H), 3.46 (s, 2H),2.68-2.75 (m, 2H), 2.70 (s, 3H), 2.53-2.56 (m, 2H), 2.40-2.46 (m, 2H).Mass spec.: 441.13 (MH)⁺.

EXAMPLE 189

3′-(((4-(4-Fluorophenyl)-1-methylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl_(3,) 500 MHz) δ 7.76-7.74 (m, 2H), 7.67 (s, 1H), 7.59-7.57(m, 2H), 7.39-7.41 (m, 2H), 7.30-7.33 (m, 2H), 6.97-7.00 (m, 2H), 4.46(s, 2H), 3.44 (s, 2H), 2.54-2.56 (m, 2H), 2.16-2.25 (m, 4H), 2.20 (s,3H), 1.97-1.99 (m, 2H). Mass spec.: 483.33 (MH)⁺.

EXAMPLE 190

3′-(((4-(3-Cyanophenyl)-1-methylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl₃, 500 MHz) δ ppm 7.76 (m, 2H), 7.67 (s, 1H), 7.63 (m, 2H),7.60 (m, 1H), 7.58 (m, 1H), 7.47 (m, 1H), 7.37-7.43 (m, 2H), 7.33 (s,1H), 4.46 (s, 2H), 3.45 (s, 2H), 2.65 (m, 2H), 2.27 (s, 3H), 2.25-2.30(m, 4H), 2.08 (m, 2H). Mass spec: 490.24 (MH)⁻.

EXAMPLE 191

3′-(((4-(3,4-Difluorophenyl)-1-methylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl₃, 500 MHz) δ ppm 7.76 (m, 2H), 7.67 (s, 1H), 7.61 (m, 2H),7.42 (s, 1H), 7.37 (s, 1H), 7.01-7.19 (br m, 3H), 4.47 (s, 2H), 3.43 (s,2H), 2.53-2.57 (br m, 2H), 1.98-2.35 (m, 9H). Mass spec.: 501.25 (MH)⁺.

EXAMPLE 192

3′-(((4-(4-Bromophenyl)-1-methylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl₃, 500 MHz) δ ppm 7.76 (m, 2H), 7.67 (s, 1H), 7.62 (m, 2H),7.45 (s, 1H), 7.42 (s, 1H), 7.35 (m, 2H), 7.18-7.27 (m, 2H), 4.47 (s,2H), 3.45 (s, 2H), 2.35-2.55 (br m, 2H), 1.55 (m, 9H). Mass spec.:543.16 (MH)⁺.

EXAMPLE 193

3′-(((4-(3-Bromophenyl)-1-methylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl₃, 500 MHz) δ ppm 7.78 (m, 2H), 7.67 (s, 1H), 7.60 (m, 2H),7.45 (m, 3H), 7.37 (s, 1H), 7.22 (s, 1H), 7.20 (s, 1H), 4.46 (s, 2H),3.44 (s, 2H), 2.14-2.45 (br m, 7H), 1.48-1.53 (br m, 4H). Mass spec.:543.16 (MH)⁺.

EXAMPLE 194

3′-(((4-(4-Cyanophenyl)-1-methylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl₃, 500 MHz) δ ppm 7.78 (m, 2H), 7.60-7.69 (m, 5H), 7.45 (m,2H), 7.28 (br m, 2H), 4.46 (s, 2H), 3.48 (s, 1H), 1.62-2.55 (br m, 12H).Mass spec.: 490.14 (MH)⁺.

EXAMPLE 195

3′-(((4-(3-Chlorophenyl)-1-methylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl₃, 500 MHz) δ ppm 7.75 (m, 2H), 7.66 (s, 1H), 7.60 (m, 2H),7.42 (s, 1H), 7.38 (s, 1H), 7.32 (s, 1H), 7.23 (m, 2H), 7.16 (m, 1H),4.46 (s, 2H), 3.46 (s, 2H), 2.74 (br m, 1H), 1.98-2.35 (br m, 10H). Massspec.: 499.06 (MH)⁺.

EXAMPLE 196

3′-(((1-Methyl-4-(3-(trifluoromethyl)phenyl)piperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl₃, 500 MHz) δ ppm 7.74 (m, 2H), 7.66 (s, 1H), 7.58 (m, 2H),7.54 (m, 1H), 7.42 (m, 2H), 7.35 (s, 1H), 4.45 (s, 2H), 3.48 (s, 2H),2.66 (br m, 1H), 1.98-2.30 (br m, 10H). Mass spec.: 533.19 (MH)⁺.

EXAMPLE 197

3′-(((4-(4-(Furan-2-yl)phenyl)-1-methylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl₃, 500 MHz) δ ppm 7.55-7.64 (m, 5H), 7.47-7.52 (m, 3H), 7.38(s, 1H), 7.34 (m, 3H), 6.62 (m, 1H), 6.52 (m, 1H), 4.47 (s, 2H), 3.47(s, 2H), 2.74-3.01 (br m, 2H), 1.98-2.30 (br m, 9H). Mass spec.: 531.11(MH)⁺.

EXAMPLE 198

3′-(((4-(3-Methoxyphenyl)-1-methylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl₃, 500 MHz) δ ppm 7.75 (m, 2H), 7.66 (s, 1H), 7.62 (m, 2H),7.48 (s, 1H), 7.37 (s, 1H), 7.26 (m, 1H), 6.92 (m, 1H), 6.88 (m, 1H),6.76 (m, 1H), 4.45 (s, 2H), 3.75 (s, 3H), 3.46 (s, 2H), 2.80 (br m, 2H),2.15-2.81 (m, 9H). Mass spec.: 495.12 (MH)⁺.

EXAMPLE 199

4-(((4′-Fluoro-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(4-fluorophenyl)-1-methylpiperidine.¹H-NMR (CDCl₃, 500 MHz) δ 7.63 (s, 1H), 7.46 (m, 2H), 7.39 (s, 1H), 7.32(m, 3H), 7.15 (m, 2H), 7.00 (m, 2H), 4.45 (s, 2H), 3.44 (s, 2H), 2.58(m, 2H), 2.22 (s, 3H), 2.20 (m, 4H), 2.00 (m, 2H); ¹³C NMR (126 MHz,CDCl₃) δ ppm 164.0, 162.3, 162.0, 160.4, 141.2, 140.4, 139.6, 135.8,131.5, 131.2, 128.9 (m), 128.8 (m), 124.1 (q, J=273 Hz), 122.8 (q, J=3.8Hz), 122.6 (q, J=3.8 Hz), 116.1, 115.9, 115.1, 115.0, 79.6 (br), 72.4,51.9, 46.2, 40.4, 32.6. Mass spec.: 476.34 (MH)⁺. Accurate mass spec.:m/z 476.2013 [MH]⁺, Δ=0.0 ppm.

EXAMPLE 200

4-(((4′,5-Difluorobiphenyl-3-yl)methoxy)methyl)-1-methyl-4-phenylpiperidine.¹H-NMR (CDCl_(3,) 500 MHz) δ 7.74-7.76 (m, 2H), 7.66 (s, 1H), 7.58-7.60(m, 2H), 7.44 (s, 1H), 7.41 (s, 1H), 7.36-7.38 (m, 2H), 7.30-7.33 (m,2H), 7.18-7.21 (m, 1H), 4.45 (s, 2H), 3.48 (s, 2H), 2.58-2.60 (m, 2H),2.17-2.28 (m, 4H), 2.21 (s, 3H), 1.98-2.08 (m, 2H). ¹³C-NMR (CDCl₃, 126MHz) δ 164.0 (d, J=51.8 Hz), 162.1 (d, J=52.8 Hz), 142.3, 142.0, 136.1,128.8, 128.3, 127.4, 126.1, 121.1, 115.9, 115.7, 112.8, 112.6, 72.5,52.1, 46.3, 40.9, 32.5. Mass spec.: 408.16 (MH)⁺. Accurate mass spec.:m/z 408.2157 [MH]⁺, Δ=4.4 ppm.

EXAMPLE 201

3′-Fluoro-540-(((1-methyl-4-phenylpiperidin-4-yl)methoxy)methyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl_(3,) 500 MHz) δ 7.72 (s, 1H), 7.71 (s, 1H), 7.57 (s, 1H),7.56 (s, 1H), 7.31-7.38 (m, 4H), 7.19-7.22 (m, 1H), 7.11-7.13 (m, 1H),7.06 (s, 1H), 6.82-6.84 (s, 1H), 4.39 (s, 2H), 3.45 (s, 2H), 2.59-2.62(m, 2H), 2.17-2.27 (m, 4H), 2.21 (s, 3H), 2.00-2.05 (m, 2H). Mass spec.:415.18 (MH)⁺.

EXAMPLE 202

4-(((4′-Methoxy-3′-methyl-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-1-methyl-4-phenylpiperidine.¹H-NMR (CD₃OD, 500 MHz) δ 7.69 (m, 1H), 7.58 (m, 1H), 7.28-7.53 (m, 8H),6.99-7.02 (m, 1H), 4.52 (s, 2H), 3.89 (s, 3H), 3.48 (s, 2H), 3.44 (m,2H), 2.66-2.93 (m, 4H), 2.75 (s, 3H), 2.28 (s, 3H), 2.12-2.22 (m, 2H).Mass spec.: 484.11 (MH)⁺. Accurate mass spec.: m/z 484.2471 [MH]⁺, Δ=1.6ppm.

EXAMPLE 203

4-(((2′,3′-Difluoro-4′-methoxy-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-1-methyl-4-phenylpiperidine.¹H-NMR (CD₃OD, 500 MHz) δ 7.63 (s, 1H), 7.40-7.44 (m, 4H), 7.28-7.32 (m,2H), 7.14-7.18 (m, 2H), 7.02-7.07 (m, 1H), 4.48 (s, 2H), 3.97 (s, 3H),3.51 (s, 2H), 2.61 (m, 2H), 2.22-2.30 (m, 4H), 2.19 (s, 3H), 2.02-2.07(m, 2H). Mass spec.: 506.15 (MH)⁺. Accurate mass spec.: m/z 506.2096[MH]⁺, Δ=4.4 ppm.

EXAMPLE 204

4-(((3′,5′-difluoro-4′-methoxy-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-1-methyl-4-phenylpiperidine.¹H-NMR (CD₃OD, 500 MHz) δ 7.73-7.75 (m, 1H), 7.57 (s, 1H), 7.43-7.50 (m,5H), 7.21-7.33 (m, 3H), 4.55 (s, 2H), 4.04 (s, 3H), 3.49 (s, 2H), 3.46(m, 2H), 2.84-2.90 (m, 2H), 2.76 (s, 3H), 2.70-2.73 (m, 2H), 2.10-2.23(m, 2H). Mass spec.: 505.93 (MH)⁺. Accurate mass spec.: m/z 506.2116[MH]⁺, Δ=0.5 ppm.

EXAMPLE 205

4-(((2′,5′-Difluoro-4′-methoxy-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-1-methyl-4-phenylpiperidine.¹H-NMR (CD₃OD, 500 MHz) δ 7.65 (s, 1H), 7.40-7.42 (m, 4H), 7.28-7.33 (m,2H), 7.03-7.20 (m, 3H), 4.48 (s, 2H), 3.95 (s, 3H), 3.50 (s, 2H), 2.65(m, 2H), 2.30 (m, 4H), 2.18 (s, 3H), 2.04-2.08 (m, 2H). Mass spec.:506.19 (MH)⁺. Accurate mass spec.: m/z 506.2110 [MH]⁺, Δ=1.7 ppm.

EXAMPLE 206

3-Methoxy-3′-(((1-methyl-4-phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CD₃OD, 500 MHz) δ 7.81 (s, 1H), 7.69-7.73 (m, 1H), 7.64 (s, 1H),7.51 (s, 1H), 7.40-7.43 (m, 2H), 7.25-7.33 (m, 4H), 7.15-7.20 (m, 1H),4.53 (s, 2H), 4.05 (s, 3H), 3.53 (s, 2H), 2.60-2.65 (m, 2H), 2.24-2.30(m, 4H), 2.19 (s, 3H), 2.01-2.10 (m, 2H). Mass spec.: 495.20 (MH)⁺.

EXAMPLE 207

2,5-Difluoro-3′-(((1-methyl-4-phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CD₃OD, 500 MHz) δ 7.79-7.81 (m, 2H), 7.55-7.62 (m, 3H),7.41-7.50 (m, 4H), 7.28-7.29 (m, 1H), 4.58 (s, 2H), 3.49 (s, 2H),3.45-3.49 (m, 2H), 2.85-2.90 (m, 2H), 2.76 (s, 3H), 2.71-2.74 (m, 2H),2.17-2.22 (m, 2H). Mass spec.: 501.11 (MH)⁺. Accurate mass spec.: m/z501.1964 [MH]⁺, Δ=0.3 ppm.

EXAMPLE 208

(±)-3′-(1-((4-Phenylpiperidin-4-yl)methoxy)ethyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.(±)-tert-Butyl4-((1-(4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate(36 mg, 0.064 mmol) was dissolved in trifluoroacetic acid (33% indichloromethane, 1.5 mL). The resulting solution was stirred at roomtemperature for 1 h and concentrated. The crude salt was loaded onto anSCX cartridge in methanol. The cartridge was flushed with severalvolumes of methanol which was discarded. The product was eluted with 2 Mammonia in methanol and concentrated to give 29 mg (98%) as a colorlessfilm. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.73 (d, J=8.6 Hz, 2H), 7.64 (s,1H), 7.55 (d, J=8.6 Hz, 2H), 7.38 (s, 2H), 7.20-7.35 (m, 4H), 7.16 (m,1H), 4.29 (q, J=6.4 Hz, 1H), 3.46 (s, 1H), 3.33 (d, J=9.2 Hz, 1H), 3.25(d, J=8.9 Hz, 1H), 2.90 (m, 2H), 2.73 (m, 2H), 2.00-2.25 (m, 2H),1.80-1.99 (m, 2H), 1.35 (d, J=6.4 Hz, 3H). Mass spec.: 465.20 (MH)⁺.Accurate mass spec.: m/z 465.2136 [MH]⁺, Δ=3.8 ppm.

EXAMPLE 209

(±)-3′-(1-((1-Methyl-4-phenylpiperidin-4-yl)methoxy)ethyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.To a suspension of(±)-3′-(1-((4-phenylpiperidin-4-yl)methoxy)ethyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile(15 mg, 0.032 mmol) and sodium cyanoborohydride (10.2 mg, 0.16 mmol) inacetonitrile (1 mL) at 0° C. was added formalin (0.1 mL, 3.6 mmol). Theice bath was removed and stirring continued for 1 h. The reaction wasconcentrated and loaded onto an SCX cartridge in methanol. The cartridgewas flushed with several volumes of methanol which was discarded. Theproduct was eluted with 2 M ammonia in methanol and concentrated to give13 mg (84%) as a colorless film. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.74 (m,2H), 7.64 (s, 1H), 7.56 (m, 2H), 7.37 (s, 2H), 7.22-7.35 (m, 5H), 7.16(m, 1H), 4.29 (q, J=6.4 Hz, 1H), 3.32 (d, J=8.9 Hz, 1H), 3.25 (d, J=8.9Hz, 1H), 2.61 (m, 2H), 2.11-2.35 (m, 7H), 1.95-2.10 (m, 2H), 1.34 (m,3H). Mass spec.: 479.30 (MH)⁺. Accurate mass spec.: m/z 479.2300 [MH]⁺,Δ=2.1 ppm.

EXAMPLE 210

(R)-3′-(1-((4-phenylpiperidin-4-yl)methoxy)ethyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.(R)-tert-Butyl4-((1-(4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate(10 mg, 0.018 mmol) was dissolved in trifluoroacetic acid (33% indichloromethane, 1.5 mL). The resulting solution was stirred at roomtemperature for 1 h and concentrated. The crude salt was loaded onto anSCX cartridge in methanol. The cartridge was flushed with severalvolumes of methanol which was discarded. The product was eluted with 2 Mammonia in methanol and concentrated to give 7.2 mg (88%) as a colorlessfilm. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.73 (d, J=8.6 Hz, 2H), 7.64 (s,1H), 7.55 (d, J=8.6 Hz, 2H), 7.38 (s, 2H), 7.20-7.35 (m, 4H), 7.16 (m,1H), 4.29 (q, J=6.4 Hz, 1H), 3.46 (s, 1H), 3.33 (d, J=9.2 Hz, 1H), 3.25(d, J=8.9 Hz, 1H), 2.90 (m, 2H), 2.73 (m, 2H), 2.00-2.25 (m, 2H),1.80-1.99 (m, 2H), 1.35 (d, J=6.4 Hz, 3H). Mass spec.: 465.20 (MH)⁺.Accurate mass spec.: m/z 465.2136 [MH]⁺, Δ=3.8 ppm.

EXAMPLE 211

3′-Bromo-5′-(((4-phenylpiperidin-4-yl)methoxy)methyl)biphenyl-4-carbonitrile.tert-Butyl4-(((5-bromo-4′-cyanobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate(24.3 mg, 0.04 mmol) was treated with a trifluoroacetic acid/methylenechloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuoand the resulting crude mixture passed through a strong cation exchangecolumn. After washing the column with several volumes of methanol, theproduct was eluted by washing the column with 2 M ammonia in methanol.The solvent was evaporated and the compound purified by columnchromatography (10% ammonia in methanol/methylene chloride) to afford13.2 mg (72%). ¹H-NMR (CDCl_(3,) 500 MHz) δ 7.71-7.73 (m, 2H), 7.31-7.37(m, 5H), 7.28 (s, 1H), 7.20-7.22 (m, 2H), 4.38 (s, 2H), 3.44 (s, 2H),2.91-2.94 (m, 2H), 2.74-2.78 (m, 2H), 2.16-2.20 (m, 2H), 1.89-1.93 (m,2H). Mass spec.: 463.09 (MH)⁺. Accurate mass spec.: m/z 463.1205 [MH]⁺,Δ=1.0 ppm.

EXAMPLE 212

6-(3-(((4-Phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)phenyl)nicotinonitrile.To a solution of tert-butyl4-phenyl-4-((3-(tributylstannyl)-5-(trifluoromethyl)benzyloxy)methyl)piperidine-1-carboxylate(60 mg, 0.081 mmol) and 6-bromonicotinonitrile (16.4 mg, 0.089 mmol) inacetonitrile (1 mL) was added bis(triphenylphosphine)palladium(II)chloride (2.28 mg, 3.25 μmol). The reaction was heated at 150° C. viamicrowave for 1 h. The reaction was concentrated and purified by columnchromatography (12%→25% ethyl acetate/hexanes) gave the Boc-protectedamine: Mass spec.: 552.31 (MH)⁺. The carbamate was dissolved intrifluoroacetic acid (33% in dichloromethane, 1.5 mL), stirred for 1 h,and concentrated. The crude trifluoroacetic acid salt was loaded onto astrong cation exchange cartridge which was flushed with several volumesof methanol which were discarded. The product was eluted using 2 Mammonia in methanol and concentrated. The reaction was repurified bypreparative HPLC (TFA/MeOH/Water). The fraction was concentrated, loadedonto a strong cation exchange cartridge, and flushed with severalvolumes of methanol which were discarded. The product was eluted with 2M ammonia in methanol and concentrated to give 9 mg (25%) as a colorlessoil. ¹H-NMR (CDCl₃, 500 MHz) δ 8.95 (s, 1H), 8.20 (s, 1H), 8.04 (m, 1H),7.93 (s, 1H), 7.76 (d, J=8.2 Hz, 1H), 7.49 (s, 1H), 7.30-7.45 (m, 4H),7.22 (m, 1H), 4.48 (s, 2H), 3.48 (s, 2H), 2.94 (m, 2H), 2.77 (m, 2H),2.21 (m, 2H), 1.94 (m, 2H). Mass spec.: 452.27 (MH)⁺. Accurate massspec.: m/z 452.1934 [MH]⁺, Δ=3.5 ppm.

EXAMPLE 213

3-Fluoro-3′-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl₃, 500 MHz) δ 7.71 (m, 1H), 7.65 (s, 1H), 7.28-7.47 (m, 8H),7.20 (m, 1H), 4.46 (s, 2H), 3.49 (s, 2H), 2.91 (m, 2H), 2.76 (m, 2H),2.20 (m, 2H), 1.88 (m, 2H), 1.59 (bs, 1H). Mass spec.: 469.37 (MH)⁺.Accurate mass spec.: m/z 469.1924 [MH]⁺, Δ=4.5 ppm.

EXAMPLE 214

2-Methyl-3′-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl₃, 500 MHz) δ 7.58 (s, 1H), 7.55 (d, J=7.9 Hz, 1H),7.33-7.44 (m, 4H), 7.20-7.31 (m, 3H), 7.10-7.18 (m, 2H), 4.44 (s, 2H),3.46 (s, 2H), 2.90 (m, 2H), 2.75 (m, 2H), 2.22 (s, 3H), 2.19 (m, 2H),1.88 (m, 2H), 1.59 (bs, 1H). Mass spec.: 465.31 (MH)⁻. Accurate massspec.: m/z 465.2166 [MH]⁺, Δ=2.6 ppm.

EXAMPLE 215

3-Methoxy-6-(3-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)phenyl)pyridazine.To a solution of tert-butyl4-phenyl-4-((3-(tributylstannyl)-5-(trifluoromethyl)benzyloxy)methyl)piperidine-1-carboxylate(100 mg, 0.135 mmol) and 3-chloro-6-methoxypyridazine (22 mg, 0.15 mmol)in acetonitrile (1.2 mL) was added bis(triphenylphosphine)palladium(II)chloride (3.80 mg, 5.42 μmol). The reaction was heated at 150° C. viamicrowave for 1 h. The reaction was diluted with pentane, filtered, andconcentrated. Purification by column chromatography (12%→25% ethylacetate/hexanes) gave the Boc-protected amine. The carbamate wasdissolved in trifluoroacetic acid (33% in dichloromethane, 1.5 mL),stirred for 1 h, and concentrated. The reaction was purified bypreparative HPLC (TFA/MeOH/Water) to give the product as itstrifluoroacetic acid salt. The salt was loaded onto a strong cationexchange cartridge in methanol and flushed with several volumes ofmethanol which were discarded. The product was eluted with 2 M ammoniain methanol and concentrated to give 10 mg (16%). ¹H-NMR (CDCl₃, 500MHz) δ 8.20 (s, 1H), 8.06 (m, 2H), 7.61 (s, 1H), 7.49 (m, 2H), 7.42 (m,2H), 7.34 (d, J=9.2 Hz, 1H), 7.29 (m, 1H), 4.60 (s, 2H), 4.19 (s, 3H),3.57 (s, 2H), 3.36 (m, 2H), 2.97 (m, 2H), 2.57 (m, 2H), 2.25 (m, 2H).Mass spec.: 458.19 (MH)⁺. Accurate mass spec.: m/z 458.2061 [MH]⁺, Δ=1.2ppm.

EXAMPLE 216

3-Methyl-3′-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl₃, 500 MHz) δ 7.82 (s, 1H), 7.77 (d, J=7.9 Hz, 1H), 7.65 (s,2H), 7.56 (m, 1H), 7.53 (s, 1H), 7.48 (m, 2H), 7.41 (m, 2H), 7.28 (m,1H), 4.57 (s, 2H), 3.56 (s, 2H), 3.36 (m, 2H), 2.97 (m, 2H), 2.63 (s,3H), 2.56 (m, 2H), 2.22 (m, 2H). Mass spec.: 465.19 (MH)⁺. Accurate massspec.: m/z 465.2152 [MH]⁺, Δ=0.4 ppm.

EXAMPLE 217

3-Chloro-3′-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl₃, 500 MHz) δ 7.75-7.95 (m, 3H), 7.71 (m, 1H), 7.51-7.65 (m,2H), 7.32-7.51 (m, 4H), 7.28 (m, 1H), 4.58 (s, 2H), 3.57 (s, 2H), 3.36(m, 2H), 2.97 (m, 2H), 2.56 (m, 2H), 2.21 (m, 2H). Mass spec.: 485.11(MH)⁺. Accurate mass spec.: m/z 485.1627 [MH]⁺, Δ=4.0 ppm.

EXAMPLE 218

2,3,5,6-Tetrafluoro-3′-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl₃, 500 MHz) δ 7.78 (s, 1H), 7.67 (s, 1H), 7.48 (m, 3H), 7.40(m, 2H), 7.25 (m, 1H), 4.59 (s, 2H), 3.56 (s, 2H), 3.35 (m, 2H), 2.96(m, 2H), 2.57 (m, 2H), 2.20 (m, 2H). Mass spec.: 523.12 (MH)⁺. Accuratemass spec.: m/z 523.1608 [MH]⁺, Δ=2.4 ppm.

EXAMPLE 219

3,5-Difluoro-3′-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl₃, 500 MHz) δ 7.91 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 7.55(m, 2H), 7.48 (m, 2H), 7.42 (m, 2H), 7.29 (m, 1H), 4.59 (s, 2H), 3.57(s, 2H), 3.36 (m, 2H), 2.97 (m, 2H), 2.57 (m, 2H), 2.21 (m, 2H). Massspec.: 487.16 (MH)⁺. Accurate mass spec.: m/z 487.1792 [MH]⁺, Δ=3.4 ppm.

EXAMPLE 220

2-Chloro-5-(3-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)phenyl)pyrimidine.¹H-NMR (CDCl₃, 500 MHz) δ 8.95 (s, 2H), 7.94 (s, 1H), 7.64 (s, 1H), 7.61(s, 1H), 7.49 (m, 2H), 7.41 (m, 2H), 7.28 (m, 1H), 4.60 (s, 2H), 3.56(s, 2H), 3.36 (m, 2H), 2.96 (m, 2H), 2.57 (m, 2H), 2.20 (m, 2H). Massspec.: 462.12 (MH)⁺. Accurate mass spec.: m/z 462.1579 [MH]⁺, Δ=4.1 ppm.

EXAMPLE 221

4′-Methoxy-3′-methyl-5′-(((4-phenylpiperidin-4-yl)methoxy)methyl)biphenyl-4-carbonitrile.tert-Butyl4-((5-bromo-2-methoxy-3-methylbenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate(65 mg, 0.13 mmol), 4-cyanophenylboronic acid (76.4 mg, 0.52 mmol), andtetrakis(triphenylphosphine) palladium(0) (20 mg, 0.01 mmol) werecombined in dry tetrahydrofuran (2 mL) in a microwave tube and sealed.After flushing with nitrogen, 0.46 mL of a 1 N potassium hydroxideaqueous solution was introduced. The mixture was heated at 120° C. for 1h via microwave. After cooling to room temperature, the reaction mixturewas concentrated and treated with a trifluoroacetic acid/methylenechloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuoand the resulting crude mixture passed through a strong cation exchangecolumn. After washing the column with several volumes of methanol, theproduct was eluted by washing the column with 2 M ammonia in methanoland concentrated to afford 28 mg (51%). ¹H-NMR (CDCl_(3,) 500 MHz) δ7.69 (s, 1H), 7.68 (s, 1H), 7.55 (s, 1H), 7.53 (s, 1H), 7.37 (s, 1H),7.36 (s, 1H), 7.27-7.30 (m, 3H), 7.17-7.20 (m, 2H), 4.46 (s, 2H), 3.61(s, 3H), 3.50 (s, 2H), 2.89-2.92 (m, 2H), 2.72-2.76 (m, 2H), 2.31 (s,3H), 2.16-2.19 (m, 2H), 1.88-1.93 (m, 2H). ¹³C-NMR (CDCl₃, 126 MHz) δ157.1, 145.4, 144.4, 134.7, 132.5, 132.4, 131.7, 129.2, 128.3, 127.6,127.4, 126.1, 125.8, 119.1, 110.6, 80.2, 68.2, 60.9, 42.7, 41.9, 33.6,16.2. Mass spec.: 427.42 (MH)⁺. Accurate mass spec.: m/z 427.2378 [MH]⁺,Δ=1.8 ppm.

EXAMPLE 222

3,5-Difluoro-3′-(((1-methyl-4-phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.To a solution of tert-butyl4-phenyl-4-((3-(tributylstannyl)-5-(trifluoromethyl)benzyloxy)methyl)piperidine-1-carboxylate(100 mg, 0.135 mmol) and 4-bromo-2,6-difluorobenzonitrile (33 mg, 0.15mmol) in acetonitrile (1.2 mL) was addedbis(triphenylphosphine)palladium(II) chloride (3.80 mg, 5.42 μmol). Thereaction was heated at 150° C. via microwave for 1 h. The reaction wasdiluted with pentane, filtered, and concentrated. Purification by columnchromatography (12%→25% ethyl acetate/hexanes) gave the Boc-protectedamine. The carbamate was dissolved in trifluoroacetic acid (33% indichloromethane, 1.5 mL), stirred for 1 h, and concentrated. The crudetrifluoroacetic acid salt was dissolved in acetonitrile (2.5 mL), cooledto 0° C., and treated with sodium cyanoborohydride (25.5 mg, 0.406mmol), and then with formalin (0.25 mL). The crude product was purifiedby HPLC and concentrated. The trifluoroacetic acid salt was loaded ontoa strong cation exchange cartridge and flushed with methanol which wasdiscarded. The product was eluted with 2 M ammonia in methanol andconcentrated to give 21 mg (31%). ¹H-NMR (CDCl₃, 500 MHz) δ 7.62 (s,1H), 7.45 (s, 1H), 7.30-7.40 (m, 5H), 7.21 (m, 1H), 7.17 (s, 1H), 7.16(s, 1H), 4.46 (s, 2H), 3.48 (s, 2H), 2.58 (m, 2H), 2.27 (m, 2H), 2.20(s, 3H), 2.19 (m, 2H), 1.98 (m, 2H); ¹³C NMR (126 MHz, CDCl₃) δ ppm164.1, 164.5, 162.51, 162.47, 147.7 (t, J=9.6 Hz), 141.7, 138.0 (m),132.0 (q, J=33 Hz), 128.8, 128.3, 127.4, 126.3, 124.9 (q, J=3.8 Hz),123.7 (q, J=273 Hz), 122.8 (q, J=3.8 Hz), 111.01, 110.98, 110.84,110.82, 109.1, 80.3 (br), 77.7, 72.0, 52.0, 46.3, 40.9, 32.6. Massspec.: 501.14 (MH)⁺. Accurate mass spec.: m/z 501.1974 [MH]⁺, Δ=1.7 ppm.

EXAMPLE 223

2,3,5,6-Tetrafluoro-3′-(((1-methyl-4-phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl₃, 500 MHz) δ 7.55 (s, 1H), 7.50 (s, 1H), 7.36 (m, 2H),7.25-7.32 (m, 3H), 7.13 (m, 1H), 4.46 (s, 2H), 3.47 (s, 2H), 2.57 (m,2H), 2.26 (m, 2H), 2.19 (s, 3H), 2.18 (m, 2H), 1.98 (m, 2H). Mass spec.:537.13 (MH)⁺. Accurate mass spec.: m/z 537.1755 [MH]⁺, Δ=4.1 ppm.

EXAMPLE 224

3-Chloro-3′-(((1-methyl-4-phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl₃, 500 MHz) δ 7.75 (d, J=8.2 Hz, 1H), 7.63 (m, 2H), 7.48(dd, J=7.9, 1.8 Hz, 1H), 7.42 (s, 1H), 7.39 (s, 1H), 7.36 (m, 2H), 7.32(m, 2H), 7.19 (m, 1H), 4.45 (s, 2H), 3.48 (s, 2H), 2.59 (m, 2H), 2.27(m, 2H), 2.20 (s, 3H), 2.19 (m, 2H), 1.99 (m, 2H); ¹³C NMR (126 MHz,CDCl₃) δ ppm 145.6, 143.8, 141.4, 138.9, 137.6, 134.5, 131.8 (q, J=33Hz), 129.0, 128.7, 128.3, 127.4, 126.2, 126.0, 124.4 (q, J=3.8 Hz),123.8 (q, J=273 Hz), 123.0 (q, J=2.9 Hz), 115.9, 112.7, 80.1 (br), 77.7,72.1, 52.0, 50.8, 46.3, 40.9, 32.5. Mass spec.: 499.14 (MH)⁺. Accuratemass spec.: m/z 499.1776 [MH]⁺, Δ=2.4 ppm.

EXAMPLE 225

3-Methyl-3′-(((1-methyl-4-phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl₃, 500 MHz) δ 7.68 (d, J=8.2 Hz, 1H), 7.65 (s, 1H), 7.45 (s,1H), 7.44 (s, 1H), 7.34-7.42 (m, 4H), 7.31 (m, 2H), 7.19 (m, 1H), 4.44(s, 2H), 3.47 (s, 2H), 2.60 (m, 2H), 2.27 (m, 2H), 2.21 (s, 3H), 2.20(m, 2H), 2.01 (m, 2H); ¹³C NMR (126 MHz, CDCl₃) δ ppm 144.0, 142.7,140.9, 140.3, 133.1, 131.6 (q, J=33 Hz), 129.0, 128.3, 127.4, 126.2,125.2, 124.0 (q, J=273 Hz), 123.8 (q, J=3.8 Hz), 123.0 (q, J=2.9 Hz),118.0, 112.4, 80.0 (br), 77.7, 72.3, 52.0, 46.2, 40.9, 32.4, 20.7. Massspec.: 479.19 (MH). Accurate mass spec.: m/z 479.2322 [MH]⁺, Δ=2.5 ppm.

EXAMPLE 226

(R)-3′-(1-((1-Methyl-4-phenylpiperidin-4-yl)methoxy)ethyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.(R)-tert-Butyl4-((1-(4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate(300 mg, 0.53 mmol) was treated with a trifluoroacetic acid/methylenechloride mixture (1:1, 6 mL) for 1 h. The solvent was removed in vacuoand the resulting crude product dissolved in acetonitrile (5 mL), cooledto 0° C. and treated with formaldehyde (37 wt. % solution in water, 1.1mL). The reaction was treated with sodium cyanoborohydride (163 mg, 2.58mmol) and a few drops of acetic acid. The reaction was stirred at 0° C.for 30 min and at room temperature for 1 h. The solvent was removed invacuo and the resulting crude mixture passed through a strong cationexchange column. After washing the column with several volumes ofmethanol, the product was eluted by washing the column with 2 M ammoniain methanol. The solvents were evaporated to afford 222 mg (73%). ¹H-NMR(CDCl_(3,) 300 MHz) δ 7.71 (s, 1H), 7.68 (s, 1H), 7.62 (s, 1H), 7.53 (s,1H), 7.51 (s, 1H), 7.21-7.35 (m, 6H), 7.09-7.14 (m, 1H), 4.27 (q, J=6.6Hz, 1H), 3.29 (d, J=9.2 Hz, 1H), 3.24 (d, J=8.8 Hz, 1H), 2.50-2.57 (m,2H), 2.15 (s, 3H), 1.93-2.22 (m, 6H), 1.32 (m, 3H); ¹³C-NMR (CDCl₃, 76MHz) δ 146.5, 149.8, 140.0, 132.6, 131.4 (d, J=32.2 Hz), 128.0, 127.8,127.7, 125.9, 123.8 (q, J=272.4 Hz), 122.8, 122.7, 122.0, 118.5, 111.6,51.8, 50.2, 46.1, 40.1, 32.3, 31.9, 23.9. Mass spec.: 479.19 (MH)⁻.

EXAMPLE 227

3′-(((1-Ethyl-4-phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.3′-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile(25.0 mg, 0.05 mmol) and acetaldehyde (0.25 mL, 4.31 mmol) were combinedin acetonitrile (2.0 mL) and cooled to 0° C. The reaction was treatedwith sodium cyanoborohydride (14.0 mg, 0.23 mmol) and a few drops ofacetic acid. The reaction was stirred at 0° C. for 30 min and at roomtemperature for 1 h. The solvent was removed in vacuo and the resultingcrude mixture passed through a strong cation exchange column. Afterwashing the column with several volumes of methanol, the product waseluted by washing the column with 2 M ammonia in methanol. The solventswere evaporated to afford 17 mg (79%). ¹H-NMR (CDCl_(3,) 500 MHz) δ7.74-7.75 (m, 2H), 7.66 (s, 1H), 7.59-7.60 (m, 2H), 7.44 (s, 1H),7.30-7.39 (m, 5H), 7.18-7.21 (m, 1H), 4.45 (s, 2H), 3.48 (s, 2H), 2.76(s, 2H), 2.39-2.41 (m, 2H), 2.25-2.32 (m, 4H), 2.07-2.11 (m, 2H), 1.09(t, J=7.0 Hz, 3H). ¹³C-NMR (CDCl₃, 126 MHz) δ 144.0, 141.0, 140.1,132.8, 131.7 (q, J=32.6 Hz), 129.0, 128.5, 128.0, 127.4, 126.3, 124.0(q, J=272.6 Hz), 123.9, 123.0, 118.7, 111.9, 72.2, 52.5, 49.5, 41.4,32.0, 11.8. Mass spec.: 479.15 (MH)⁺.

EXAMPLE 228

3′-(((1-Isopropyl-4-phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CDCl_(3,) 500 MHz) δ 7.75 (s, 1H), 7.74 (s, 1H), 7.66 (s, 1H),7.60 (s, 1H), 7.58 (s, 1H), 7.36-7.43 (m, 4H), 7.29-7.32 (m, 2H),7.16-7.19 (m, 1H), 4.44 (s, 2H), 3.48 (s, 2H), 2.58-2.60 (m, 1H),2.25-2.32 (m, 4H), 1.97-2.02 (m, 2H), 0.99 (s, 3H), 0.97 (s, 3H).¹³C-NMR (CDCl₃, 126 MHz) δ 144.1, 141.0, 140.1, 132.8, 131.7 (q, J=32.6Hz), 129.1, 128.3, 128.0, 127.3, 126.1, 123.4 (q, J=272.6 Hz), 123.9,123.0, 122.9, 118.6, 112.0, 78.0, 72.3, 54.8, 45.3, 41.3, 32.8, 32.0,18.7. Mass spec.: 493.46 (MH)⁺. Accurate mass spec.: m/z 493.2466 [MH]⁺,Δ=0.1 ppm.

EXAMPLE 229

3′-(((1-Benzyl-4-phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.¹H-NMR (CD₃OD, 500 MHz) δ 7.84-7.86 (m, 2H), 7.81 (s, 1H), 7.74-7.76 (m,2H), 7.61 (s, 1H), 7.50 (s, 1H), 7.42-7.43 (m, 2H), 7.25-7.33 (m, 7H),7.19-7.20 (m, 1H), 4.51 (s, 2H), 3.43 (s, 2H), 3.42 (s, 2H), 2.63-2.65(m, 2H), 2.26-2.30 (m, 4H), 2.05-2.07 (m, 2H). Mass spec.: 541.23 (MH)⁺.

EXAMPLE 230

3′-(((1-Cyclopropyl-4-phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.A microwave tube was charged with3′-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile(21.5 mg, 0.05 mmol), (1-ethoxycyclopropoxy)trimethylsilane (96.5 μL,0.47 mmol), sodium cyanoborohydride (15 mg, 0.24 mmol). The tube wasflushed with nitrogen and treated with methanol (2 mL) and acetic acid(3 drops). The tube was sealed and heated at 90° C. for 1 h viamicrowave. After cooling, the reaction was concentrated and purified byflash chromatography on silica gel (10% methanol/methylene chloride) toafford 13.5 mg (55%) as a colorless oil. ¹H-NMR (CDCl_(3,) 500 MHz) δ7.76 (s, 1H), 7.74 (s, 1H), 7.66 (s, 1H), 7.60 (s, 1H), 7.58 (s, 1H),7.42 (s, 1H), 7.33-7.37 (m, 5H), 7.21-7.24 (m, 1H), 4.45 (s, 2H), 3.44(s, 2H), 3.11-3.14 (m, 2H), 2.56-2.61 (m, 2H), 2.35-2.38 (m, 2H),2.09-2.16 (m, 2H), 1.78-1.79 (m, 1H), 0.82 (m, 2H), 0.54-0.56 (m, 2H).Mass spec.: 491.44 (MH)⁺. Accurate mass spec.: m/z 491.2331 [MH]⁺, Δ=4.2ppm.

EXAMPLE 231

3′-(((4-(2,4-Difluorophenyl)-1-methylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.Prepared by Method A. Mass Spec: 501.27 (MH)⁺. LC t_(r)=1.88 min(Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H₂O/0.1% TFA→90% MeOH/10%H₂O/0.1% TFA Gradient Time=2 min, Flow rate=4 mL/min).

EXAMPLE 232

3′-(((1-Methyl-4-(pyridin-3-yl)piperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.Prepared by Method A. Mass Spec.: 466.10 (MH)⁺. LC: t_(r)=1.502 min(Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H₂O/0.1% TFA→90% MeOH/10%H₂O/0.1% TFA Gradient Time=2 min, Flow rate=4 mL/min).

EXAMPLE 233

3-Methyl-3′-(((1-methyl-4-(pyridin-3-yl)piperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.Prepared by Method A. Mass Spec.: 480.20 (MH)⁺. LC t_(r)=2.465 min(Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H₂O/0.1% TFA→90% MeOH/10%H₂O/0.1% TFA Gradient Time=3 min, Flow rate=4 mL/min).

EXAMPLE 234

3′-(((1-Methyl-4-(pyridin-4-yl)piperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.A flask was charged with tert-butyl4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(pyridin-4-yl)piperidine-1-carboxylate(50 mg, 0.091 mmol) and trifluoroacetic acid (1 mL, 13.0 mmol) indichloromethane (5 mL) at 0° C. under nitrogen. After 20 min the solventwas evaporated under reduced pressure and the resulting residue driedovernight. The resulting oil was dissolved in dichloromethane (5 mL) andtreated with formaldehyde (37 wt. % solution in water, 1.0 mL) at 0° C.After 20 min, the reaction was treated with sodium triacetoxyborohydride(77 mg, 0.363 mmol). The reaction was stirred at 0° C. for 30 min and atroom temperature for 1 h. The solvent was removed in vacuo and theresulting residue purified via preparative HPLC. The solvent wasevaporated to afford 21 mg (50%). Mass Spec: 466.10 (MH)⁺. LCt_(r)=2.325 min (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H₂O/0.1%TFA→90% MeOH/10% H₂O/0.1% TFA Gradient Time=4 min, Flow rate=4 mL/min).

EXAMPLE 235

3′-(((4-(2-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile.A flask was charged with tert-butyl4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(2-fluorophenyl)piperidine-1-carboxylate(0.125 g, 0.214 mmol) in dichloromethane (2 mL). Trifluoroacetic acid0.5 mL was added and the mixture was allowed to stir at room temperaturefor 1 hr. The reaction mixture was concentrated in vacuo. The resultingoil was dissolved in dichloromethane (3 mL) and 1 mL of a 37 wt %formaldehyde solution in water. After 5 min the reaction was treatedwith sodium triacetoxyborohydride (0.136 g, 0.64 mmol). The reaction wasstirred at room temperature for 16 h. The reaction was diluted with 4 mLdichloromethane and the organic layer was separated, dried over Na₂SO₄and evaporated in vacuo. The resulting residue was dissolved in methanoland loaded onto an SCX cartridge. The cartridge was washed with 5 mLmethanol then eluted with 2 N NH₃ in methanol. The ammonia in methanolfractions were collected and evaporated in vacuo affording 0.093 g (90%)of desired N-methyl piperidine. ¹H-NMR (CDCl₃, 400 MHz) δ ppm 7.73 (d,J=8.7 Hz, 2H), 7.65 (s, 1H), 7.58 (d, J=8.7 Hz, 2H), 7.41 (s, 1H), 7.35(s, 1H), 7.32 (m, 1H), 7.16 (m, 1H), 7.09 (m, 1H), 6.91 (m, 1H), 4.46(s, 2H), 3.69 (s, 2H), 2.57 (m, 2H), 2.37 (m, 2H), 2.24 (m, 2H), 2.21(s, 3H), 2.00 (m, 2H). Mass spec.: 483.3 (MH)⁺; LC t_(r)=3.228 min(Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H₂O/0.1% TFA→90% MeOH/10%H₂O/0.1% TFA Gradient Time=4 min, Flow rate=4 mL/min).

EXAMPLE 236

3′-Fluoro-5′-(((4-phenylpiperidin-4-yl)methoxy)methyl)biphenyl-4-carbonitrile.tert-Butyl4-((3-bromo-5-fluorobenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate(100.0 mg, 0.21 mmol), 4-cyanophenylboronic acid (93 mg, 0.63 mmol), andtetrakis(triphenylphosphine) palladium(0) (33 mg, 0.02 mmol) werecombined in dry tetrahydrofuran (3 mL) in a microwave tube and sealed.After flushing with nitrogen, 0.7 mL of a 1 N potassium hydroxideaqueous solution was introduced. The mixture was heated at 120° C. for 1h via microwave. After cooling to room temperature, the reaction mixturewas concentrated and treated with a trifluoroacetic acid/methylenechloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuoand the resulting crude mixture passed through a strong cation exchangecolumn. After washing the column with several volumes of methanol, theproduct was eluted by washing the column with 2 M ammonia in methanoland concentrated to afford 48 mg (46%). ¹H-NMR (CDCl_(3,) 500 MHz) δ7.72 (s, 1H), 7.70 (s, 1H), 7.57 (s, 1H), 7.56 (s, 1H), 7.31-7.38 (m,4H), 7.19-7.22 (m, 1H), 7.11-7.13 (m, 1H), 7.08 (s, 1H), 6.84-6.86 (s,1H), 4.40 (s, 2H), 3.45 (s, 2H), 2.89-2.93 (m, 2H), 2.73-2.78 (m, 2H),2.17-2.20 (m, 2H), 1.88-1.94 (m, 2H). ¹³C-NMR (CDCl₃, 126 MHz) δ 163.3(d, J=247.6 Hz), 144.2, 142.5, 141.2, 132.7, 128.4, 127.8, 127.3, 126.2,121.3, 118.7, 114.2, 114.0, 113.1, 111.7, 80.1, 72.3, 42.7, 41.9, 33.6.Mass spec.: 401.28 (MH)⁺. Accurate mass spec.: m/z 401.2026 [MH]⁺, Δ=0.8ppm.

EXAMPLE 237

4-(((4′,5-Difluorobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine.¹H-NMR (CDCl_(3,) 500 MHz) δ 8.97 (s, 1H), 7.42-7.46 (m, 2H), 7.32-7.39(m, 4H), 7.20-7.23 (m, 1H), 7.07-7.14 (m, 3H), 7.05 (s, 1H), 6.78-6.86(m, 1H), 4.39 (s, 2H), 3.45 (s, 2H), 2.89-2.93 (m, 2H), 2.73-2.78 (m,2H), 2.17-2.19 (m, 2H), 1.89-1.94 (m, 2H), ¹³C-NMR (CDCl₃, 126 MHz) δ164.1 (d, J=52.8 Hz), 162.1 (d, J=53.8 Hz), 144.3, 142.3, 142.0, 136.1,128.8, 128.4, 127.3, 126.2, 121.2, 115.9, 115.7, 112.8, 79.9, 72.5,42.8, 41.9, 33.6. Mass spec.: 394.3 (MH)⁺. Accurate mass spec.: m/z394.1978 [MH]⁺, Δ=1.1 ppm.

EXAMPLE 238

4-((3-Bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-(2,4-difluorophenyl)-1-methylpiperidine.tert-Butyl4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-(2,4-difluorophenyl)piperidine-1-carboxylate(200 mg, 0.35 mmol) was dissolved in methanol (5 mL). Hydrochloric acid(gas) was bubbled through for 20 seconds, then removed. The reaction wasallowed to stir for 20 min and the solvent evaporated. The resultingsolid was dissolved in dichloromethane (2 mL) and treated withformaldehyde (37 wt. % solution in water, 1.5 mL) at 0° C. After 20 minthe reaction was treated with sodium triacetoxyborohydride (297 mg, 1.4mmol). The reaction was stirred at 0° C. for 30 min and at roomtemperature for 1 h. The solvent was removed in vacuo and the resultingcrude mixture passed through a strong cation exchange column. Afterwashing the column with several volumes of methanol, the product waseluted by washing the column with 2 M ammonia in methanol. The solventswere evaporated to afford 142 mg (85%). Mass Spec: 478.07 (MH)⁺. LCt_(r)=1.885 min (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H₂O/0.1%TFA→90% MeOH/10% H₂O/0.1% TFA Gradient Time=2 min, Flow rate=4 mL/min).

1. A compound of Formula I

where: R¹ is hydrogen, alkyl, cycloalkyl, or benzyl; R² is hydrogen oralkyl; R³ is hydrogen or alkyl; R⁴ is hydrogen, alkyl, haloalkyl,hydroxy, alkoxy, haloalkoxy, cyano, or COR⁶; R⁵ is hydrogen, alkyl,haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, or COR⁶; R⁶ is hydroxy,alkoxy, benzyloxy, amino, alkylamino, dialkylamino, pyrrolidinyl,piperidinyl, piperazinyl, N-alkylpiperazinyl, or morpholinyl; Ar¹ isphenyl or pyridinyl, and is substituted with 0-2 substituents selectedfrom the group consisting of halo, alkyl, haloalkyl, cyano, phenyl andfuranyl; Ar² is phenyl substituted with 1-5 substituents or is naphthylsubstituted with 0-3 substituents where the substituents are selectedfrom the group consisting of halo, alkyl, cycloalkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, haloalkoxy, benzyloxy,alkylthio, cyano, nitro, amino, alkylamino, dialkylamino,(alkylcarbonyl)amino, (alkoxycarbonyl)amino (benzyloxycarbonyl)amino,carboxy, alkoxycarbonyl, benzyloxycarbonyl, alkylSO₂, phenyl, phenoxy,acetyl, and formyl; or Ar² is furanyl, thienyl, pyrrolyl, isoxazolyl,isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrmidinyl,pyrazinyl, triazinyl, quinolinyl, or isoquinolinyl, and is substitutedwith 0-3 substituents selected from the group consisting of amino,alkylamino, dialkylamino, oxo, halo, alkyl, haloalkyl, alkoxy,alkylthio, haloalkoxy, cyano, nitro, pyrrolidinyl, piperidinyl,piperazinyl, N-alkylpiperazinyl, and morpholinyl; or Ar² isbenzodioxolyl, dibenzofuranyl, thianthrenyl, ortrimethylenedioxybenzen-yl; or a pharmaceutically acceptable saltthereof.
 2. A compound of claim 1 where: R¹ is hydrogen or alkyl; R⁴ ishydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, or cyano; R⁵ ishydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, or cyano; Ar¹ is phenylsubstituted with 0-2 substituents selected from the group consisting ofhalo, alkyl, haloalkyl, and cyano; Ar² is phenyl substituted with 1-3substituents or is naphthyl substituted with 0-3 substituents where thesubstituents are selected from the group consisting of halo, alkyl,haloalkyl, hydroxyalkyl, hydroxy, alkoxy, alkoxyalkyl, haloalkoxy,alkylthio, cyano, nitro, amino, alkylamino, dialkylamino, phenyl,phenoxy, acetyl, and formyl; or Ar² is furanyl, thienyl, pyrrolyl,isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl,pyridazinyl, pyrmidinyl, triazinyl, quinolinyl, or isoquinolinyl, and issubstituted with 0-3 substituents selected from the group consisting ofamino, alkylamino, dialkylamino, oxo, halo, alkyl, haloalkyl, alkoxy,alkylthio, haloalkoxy, cyano, nitro, pyrrolidinyl, piperidinyl,piperazinyl, N-alkylpiperazinyl, or morpholinyl; or Ar² isbenzodioxolyl, dibenzofuranyl or thianthrenyl.
 3. A compound of claim 1where R¹ is hydrogen.
 4. A compound of claim 1 where R² and R³ arehydrogen.
 5. A compound of claim 1 where R² is methyl and R³ ishydrogen.
 6. A compound of claim 1 where Ar¹ is phenyl.
 7. A compound ofclaim 1 where Ar² is phenyl substituted with 1-5 substituents or isnaphthyl substituted with 0-3 substituents where the substituents areselected from the group consisting of halo, alkyl, cycloalkyl,haloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, haloalkoxy,benzyloxy, alkylthio, cyano, nitro, amino, alkylamino, dialkylamino,(alkylcarbonyl)amino, (alkoxycarbonyl)amino (benzyloxycarbonyl)amino,carboxy, alkoxycarbonyl, benzyloxycarbonyl, alkylSO₂, phenyl, phenoxy,acetyl, and formyl.
 8. A compound of claim 1 where Ar² is furanyl,thienyl, pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl,thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl,pyridinyl, pyridazinyl, pyrmidinyl, pyrazinyl, triazinyl, quinolinyl, orisoquinolinyl, and is substituted with 0-3 substituents selected fromthe group consisting of amino, alkylamino, dialkylamino, oxo, halo,alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitro,pyrrolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl, andmorpholinyl.
 9. A compound of claim 1 selected from the group consistingof

or a pharmaceutically acceptable salt thereof.
 10. A compositioncomprising a pharmaceutically acceptable amount of a compound of claim 1and at least one pharmaceutically acceptable carrier.
 11. A method fortreating a disorder associated with aberrant levels of tachykinins orserotonin comprising administering an effective amount of a compound ofclaim 1 to a patient afflicted with the disorder.
 12. The method ofclaim 11 where the disorder is anxiety.
 13. The method of claim 11 wherethe disorder is depression, obsessive compulsive disorder, bulimia, orpanic disorder.